WO2010059922A1 - Pyrrolidine carboxamide compounds - Google Patents

Abstract

Pyrrolidine carboxamide compounds are provided. Some such pyrrolidine carboxamide compounds include agonists of sst4 which may be useful for the treatment and prevention of pain and inflammatory disorders.

Description

PYRROLIDINE CARBOXAMIDE COMPOUNDS

FIELD OF THE INVENTION

[0001] The present invention relates to pyrrolidine carboxamide compounds, which may be useful for the treatment and prevention of pain and inflammatory disorders.

BACKGROUND OF THE INVENTION

[0002] Somatostatins, which are also known as somatotropin release inhibiting factors (SRIFs), are a family of cyclic peptides produced by endocrine, gastrointestinal, immune and neuronal cells. Somatostatins exert their effects through five SRIF receptors (SSt₁, SSt₂, SSt₃, sst₄ and SSt₅). By binding to these G-protein coupled receptors (GPCRs) on target cells, they inhibit large number of hormonal secretion, cell proliferation and neurotransmission processes. SRIF- 14 and SRIF-28, which contain 14 and 28 amino acids respectively, are two key members of the somatostatin peptide family. They bind to these five receptors with nanomolar affinity (Weckbecker et al, Nature Reviews Drug Discovery, 2003, 2, 999-1017; Pinter et al, Pharmacology & Therapeutics, 2006, 112, 440-456).

[0003] Administration of these cyclic peptides exogenously inhibits nociceptive and inflammatory processes, and this is presumably mediated via the sst₄ (Szolcsanyi et al, Br. J. of Pharmacol, 1998, 125, 916-922; Szolcsanyi et al, Br. J. of Pharmacol, 1998, 123, 936-942; Helyes et al, Br. J. of Pharmacol, 2006, 149, 405-415). More importantly, anti-nociceptive and anti-inflammatory effects have been demonstrated with a selective small molecule SSt₄ agonist, J-2156. Systemic administration of J-2156 alleviates pain and inflammatory responses in the mouse formalin paw test (FPT), rat sciatic nerve ligation model and rat Complete Freund's adjuvant (CFA) model (Sandor et al, Eur. J. Pharmacol, 2006, 539, 71-75; Helyes et al, Arthritis Rheum., 2004, 50, 1677- 1685). It has been shown that small molecule sst4 agonist J-2156 inhibits airway inflammatory processes. Efficacy on inhibiting airway inflammation and hyperreactivity was demonstrated for J-2156 in mouse models (Elekes et al, Eur. J. of Pharmacol, 2008, 578, 313-322), suggesting that sst4 agonists could be useful to treat airway inflammatory diseases such as asthma and chronic obstructive pulmonary disease (COPD). [0004] In light of the strong evidence that links sst₄ to pain and inflammation, a SSt₄ sub-type selective small molecule agonist is expected to be a useful therapeutic agent for treatment of various pain and inflammatory conditions. Further, a selective modulator will prevent or minimize the potential endocrine side effects mediated through other receptor sub-types.

[0005] Centrally acting sst₄ agonists would also be of great potential for treating several human pathologies. It has been shown that the SRIF level and SSt₄ expression level are altered in patients with Alzheimer's disease (AD), temporal lobe epilepsy, Parkinson's disease and cortical injury (Crider and Witt, Mini-Reviews in Med. Chem., 2007, 7, 213-20 and references therein). Thus, centrally acting sst₄ modulators may bring benefits to these disease conditions.

[0006] In addition, a selective sst₄ small molecule agonist, L-803,087, was shown to enhance the endozepine release in cultured rat astrocytes, and in turn linked the sst₄ agonism as a potential approach for treatment of certain neuropsychiatric disorders (Crider and Witt, Mini-Reviews in Med. Chem., 2007, 7, 213-20 and references therein).

[0007] Heptapeptide TT-232 is a tyrosine kinase inhibitor that also shows high affinity to sstl, sst2, sst3 and sst4 subtypes (Simon et al, J. of MoI. Structure: THEOCHEM, 2007, 816, 73-76). TT-232 is currently in clinical trials for cancer and its anti-inflammatory and anti-nociceptive activity was related to the agonistic activity of the sst4 subtype (Keri et al, Int. J. of Peptide Res. and Ther. 2005, 11, 3-15). The antiinflammatory and neurogenic inflammatory inhibitory activity in combination with antiproliferative activity may contribute to the favorable profile for TT-232 as an anti-cancer agent, and in turn suggests that a small sst4 agonist can be potentially useful as a combination therapy for cancer.

[0008] It has been suggested that sst4 agonist may be useful for treatment of glaucoma. A thiourea compound NNC 26-9100 was published for such potential utility (Liu et al, J. Med. Chem., 1998, 41, 4693-4705).

SUMMARY OF THE INVENTION

[0009] The present invention relates to pyrrolidine carboxamide compounds. In some embodiments, such compounds can include sst4 agonists. In some embodiments, such compounds can be useful for the treatment and prevention of pain and inflammatory disorders. [0010] Some embodiments include compounds or salts thereof of formula:

[001 IJ wherein

[0012] R¹ and R² are each independently selected from hydrogen and (Ci-C₆) alkyl or together, R¹ and R² form a (C₃-C₆) cycloalkyl;

[0013] R³ is selected from hydrogen and (Ci-C₆) alkyl;

[0014] R⁴ is selected from optionally substituted heterocyclyl and optionally substituted aryl, with the proviso that R⁴ is not para-cyanophenyl;

[0015] R⁵ is chosen from optionally substituted heterocyclyl and optionally substituted aryl, with the provisos that R⁵ is not para-methoxyphenyl or para- chlorophenyl, and that when R⁵ is pyridinyl or pyrimidinyl, R¹ must be (Ci-C₆) alkyl.

[0016] Some embodiments of the foregoing include compounds or salts thereof of formula:

[0017] wherein

[0018] R¹ and R² are each independently selected from hydrogen and (Ci-C₆) alkyl, or together R¹ and R² form a (C₃-C₆) cycloalkyl;

[0019] R³ is selected from hydrogen and (Ci-C₆) alkyl; [0020] R⁴ is selected from optionally substituted heterocyclyl and optionally substituted aryl, with the proviso that R is not para-cyanophenyl;

[0021] R⁵ is chosen from optionally substituted heterocyclyl and optionally substituted aryl; and

[0022] Y is a direct bond or -CH₂ or together, Y and R¹ can form a cyclopropane;

[0023] with the provisos that when R⁵ is pyridinyl or pyrimidinyl, R¹ must be (Ci-C₆) alkyl and that when Y is a direct bond, R⁵ is not para-methoxy phenyl or para- chlorophenyl.

[0024] Some of the foregoing include compounds or salts thereof of formula:

[0025] wherein R⁸ is selected from hydrogen, trifluoromethyl, chloro, fluoro, (Ci-C₆) alkyl, (Ci-C₆) alkyoxy and trifluoromethoxy;

[0026] R⁹ and R¹⁰ are each independently chosen from hydrogen, halogen, (C]-C₆) alkyl, trifluoromethyl, (Ci-C₆) alkoxy, trifluoromethoxy and cyano; or

[0027] R⁸ and R⁹ together, or R⁹ and R¹⁰ together, along with the phenyl to which they are attached, can form napthyl;

[0028] R^{1 1} and R¹² are each independently hydrogen, fluoro, chloro, methoxy or (Ci-C₆) alkyl; and

[0029] R¹³ is hydrogen, fluoro or methyl; or

[0030] R¹¹ and R¹² together, or R¹² and R¹³ together, along with the phenyl to which they are attached, can form napthyl.

[0031] Some embodiments include mixtures of stereoisomers or salts thereof falling within the genus described by formula I:

[0032] wherein

[0033] R¹ and R² are each independently selected from hydrogen and (Ci-C₆) alkyl or together, R¹ and R² form a (C₃-C₆) cycloalkyl;

[0034] R³ is selected from hydrogen and (Ci-C₆) alkyl;

[0035] R⁴ is selected from optionally substituted heterocyclyl and optionally substituted aryl, with the proviso that R⁴ is notpαra-cyanophenyl;

[0036] R⁵ is chosen from optionally substituted heterocyclyl and optionally substituted aryl, with the provisos that R³ is not /?αrα-methoxy phenyl or para- chlorophenyl, and that when R⁵ is pyridinyl or pyrimidinyl, R¹ must be (Ci-C₆) alkyl; and

[0037] at least 51% of said mixture contains the 3 S configuration of the pyrrolidine.

[0038] Some embodiments include mixtures and salts thereof falling within the genus described by formula:

[0039] wherein

[0040] R¹ and R² are each independently selected from hydrogen and (C]-C₆) alkyl or together, R¹ and R² form a (C₃-C₆) cycloalkyl; [0041] R³ is selected from hydrogen and (Ci-C₆) alkyl;

[0042] R⁴ is selected from optionally substituted heterocyclyl and optionally substituted aryl, with the proviso that R⁴ is notpαra-cyanophenyl; and

[0043] R³ is chosen from optionally substituted heterocyclyl and optionally substituted aryl, with the provisos that R⁵ is not /?αrα-methoxyphenyl or para- chlorophenyl, and that when R⁵ is pyridinyl or pyrimidinyl, R¹ must be (Ci-C₆) alkyl.

[0044] Some embodiments of the foregoing include mixtures or salts thereof of formula:

[0045] wherein R is selected from hydrogen, trifluoromethyl, chloro, fluoro, (Cj-C₆) alkyl, (Ci-C₆) alkyoxy and trifluoromethoxy;

[0046] R and R¹⁰ are each independently chosen from hydrogen, halogen, (C]-C₆) alkyl, trifluoromethyl, (Ci-C₆) alkoxy, trifluoromethoxy and cyano; or

[0047] R⁸ and R⁹ together, or R⁹ and R¹⁰ together, along with the phenyl to which they are attached, can form napthyl;

[0048] R^{1 1} and R¹² are each independently hydrogen, fluoro, chloro, methoxy or (Ci-C₆) alkyl; and

[0049] R¹³ is hydrogen, fluoro or methyl; or

[0050] R¹ ' and R¹² together, or R¹² and R¹³ together, along with the phenyl to which they are attached, can form napthyl.

[0051] Some embodiments include compounds or salts thereof of formula:

[0052] wherein

[0053] the configuration of the pyrrolidine ring is 3S;

[0054] R¹ and R² are each independently selected from hydrogen and (C i -C₆) alkyl, or together R¹ and R² form a (C₃-C₆) cycloalkyl;

[0055] R³ is selected from hydrogen and (Ci-C₆) alkyl;

[0056] R⁴ is selected from optionally substituted heterocyclyl and optionally substituted aryl, with the proviso that R⁴ is not/?αra-cyanophenyl;

[0057] R⁵ is chosen from optionally substituted heterocyclyl and optionally substituted aryl; and

[0058] Y is a direct bond or -CH₂ or together, Y and R¹ can form a cyclopropane;

[0059] with the provisos that when R⁵ is pyridinyl or pyrimidinyl, R¹ must be (Ci-C₆) alkyl and that when Y is a direct bond, R⁵ is not /?αrø-methoxyphenyl or par a- chlorophenyl.

[0060] Some embodiments of the foregoing include compounds or salts thereof of formula

[0061] wherein R is hydrogen, trifluoromethyl, chloro, fluoro, (C]-C₆) alkyl, (Ci-C₆) alkyloxy or trifluoromethoxy;

[0062] R⁹ and R¹⁰ are each independently chosen from hydrogen, halogen, (Ci-C₆) alkyl, trifluoromethyl, (C)-C₆) alkoxy, trifluoromethoxy and cyano; or

[0063] R⁸ and R⁹ together, or R⁹ and R¹⁰ together, along with the phenyl to which they are attached, can form napthyl;

[0064] R^{1 1} and R¹² are each independently hydrogen, fluoro, chloro, methoxy or (C₁-C₆) alkyl; and

[0065] R¹³ is hydrogen, fluoro or methyl; or

[0066] R^{1 1} and R¹² together, or R¹² and R¹³ together, along with the phenyl to which they are attached, can form napthyl.

[0067] Some embodiments include a foregoing compound, mixture or salt thereof, and a pharmaceutically acceptable carrier.

[0068] In addition to the foregoing compounds, mixtures and salts thereof, some embodiments include methods of treating disorders dependent on the modulation of sst4. Some such methods include administering a foregoing compound, mixture or salt thereof to a patient in need thereof.

[0069] Some embodiments include the use of a foregoing compound, mixture or salt thereof in the preparation of a medicament for treating a disorder dependent on the modulation of sst4. Examples of disorders modulated by sst4 include types of pain, inflammatory conditions, Alzheimer's disease, temporal lobe epilepsy, Parkinson's disease, cortical injuries, and psychiatric disorders.

BRIEF DESCRIPTION OF THE DRAWINGS

[0070] Figure IA shows an Oak Ridge Thermal Ellipsoid Program (ORTEP) plot for the crystal structure of compound 11a. Figure IB shows an embodiment of the structure of compound 11a.

DETAILED DESCRIPTION

[0071] The present invention relates to certain pyrrolidine carboxamide agonists of sst₄, which may be useful for the treatment and prevention of pain and inflammatory disorders. [0072] In some embodiments, a compound of formula I, or salt thereof is provided, wherein formula I is:

[0073] R^! and R² are each independently selected from hydrogen and (Ci-C₆) alkyl or together, R¹ and R² may form a (C₃-C₆) cycloalkyl. R³ is selected from hydrogen and (Ci-C₆) alkyl. R⁴ and R⁵ are each selected from optionally substituted heterocyclyl and optionally substituted aryl.

[0074] In some embodiments, a mixture of formula I is provided. In some embodiments, a mixture of stereoisomers of formula I is provided. In some embodiments, at least 51% of a mixture can contain the 3S configuration of the pyrrolidine.

[0075] In some embodiments, a mixture can include a racemic mixture comprising compounds of formula Ib, or salt thereof, wherein formula Ib is:

[0076] In some embodiments, a compound of formula II or salt thereof is provided, wherein formula II is:

[0077] wherein, R¹ and R^z are each independently selected from hydrogen and (C]-C₆) alkyl or together, R¹ and R² may form a (C₃-C₆) cycloalkyl; R³ is selected from hydrogen and (Cj-C₆) alkyl; R⁴ and R⁵ are each selected from optionally substituted heterocyclyl and optionally substituted aryl; Y is a direct bond or -CH₂ or together, Y and R¹ may form a cyclopropane.

[0078] In some embodiments, when R⁵ is pyridinyl or pyrimidinyl, R¹ must be (Ci-C₆) alkyl and that when Y is a direct bond, R⁵ is not /?αra-methoxyphenyl or para- chlorophenyl. In some embodiments, the configuration of the pyrrolidine ring is 3S. In some embodiments, the configuration is 4R. It will be understood that in some instances, for example, in a compound where R⁴ is a heterocyclyl with the heteroatom at the 2- position, while the absolute configuration of the substituents is the same as in the others, the nomenclature may change to 4S.

[0079] Some embodiments relate to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound and/or mixture of formula I, formula Ib, formula II, or salt thereof.

[0080] Some embodiments include methods of treating or preventing disorders dependent upon the modulation of sst₄. Some methods include administering compounds, mixtures and/or pharmaceutical compositions provided herein to a subject (e.g. human) in need thereof. Thus the present invention provides a method of treatment comprising administering a therapeutically effective amount of a compound (or pharmaceutically acceptable salt thereof), mixtures or compositions of the invention to a subject (e.g. human) in need of such treatment.

[0081] Some embodiments include methods of treating neurological discorders such as pain, Alzheimer's disease, temporal lobe epilepsy, Parkinson's, cortical injury, psychiatric disorders, and inflammatory conditions, the method comprising administering a compound (or pharmaceutically acceptable salt thereof), mixtures or compositions of the invention to a subject in need of such treatment.

[0082] Some embodiments include a compound (or pharmaceutically acceptable salt thereof), mixtures or compositions of the invention for use in therapy. Some embodiments include a compound of Formula (II) or a pharmaceutically acceptable salt thereof for use in therapy.

[0083] Some embodiments include the use of a compound (or pharmaceutically acceptable salt thereof), mixtures or compositions of the invention for use in the manufacture of a medicament for the treatment of neurological indications, psychiatric disorders and inflammatory conditions. Some embodiments include the use of a compound of formula (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of neurological indications, psychiatric disorders and inflammatory conditions. In some embodiments, a particular disorder is pain such as inflammatory pain. In some embodiments, a further disorder is Alzheimer's disease. Examples of pain that may be treated with compounds provided herein include nociception. More examples of pain that may be treated with compounds provided herein conditions include osteoarthritis, acute gout, inflammatory arthropathy, dysmenorrhoea, endometriosis, headache, migraine, postoperative pain, back pain, sciatica, sprains, strains, rheumatism, dental pain, kidney stones and fever. Examples of inflammatory confditions that can be treated with compounds provided herein include airway inflammatory conditions. Examples of airway inflammatory conditions include asthma, chronic obstructive pulmonary disesase

Definitions

[0084] Terms and substituents are given their ordinary meaning unless defined otherwise, and may be defined when introduced and retain their definitions throughout.

[0085] Alkyl (whether alone or as part of another group) includes linear, branched, or cyclic hydrocarbon structures and combinations thereof. A combination can be, for example, cyclopropylmethyl. The term can refer to alkyl of 10 or fewer carbons. Lower alkyl refers to alkyl groups of 1, 2, 3, 4, 5 and 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl and the like. Preferred alkyl and alkylene groups are those of Ci₀ or below (e.g. Ci, C₂, C₃, C₄, C₅. C₆, C₇, C₈, C₉, Cio); most preferred are lower alkyl. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of 3, 4, 5, 6, 7, and 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like. Representative alkyl groups include linear or branched Ci to C₆ alkyl, such as Ci to C₃ alkyl, for example methyl or ethyl. Representative cycloalkyl groups include C₃ to C₆ cycloalkyl, such as c-propyl, c-butyl, c-pentyl, c-hexyl.

[0086] Ci to C₂₀ Hydrocarbon (e.g. Ci, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, Ci₀, etc.) includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl. Hydrocarbon refers to any substituent comprised of hydrogen and carbon as the only elemental constituents.

[0087] Unless otherwise specified, the term "carbocycle" includes ring systems in which the ring atoms are all carbon atoms of any oxidation state. Thus (C₃- C]₀) carbocycle refers to such systems as cyclopropane, benzene and cyclohexene; (C₈- C]₂) carbopoly cycle refers to such systems as norbornane, decalin, indane and naphthalene. Carbocycle, not otherwise limited, refers to monocycles, bicycles and polycycles.

[0088] Alkoxy or alkoxyl refers to groups of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms of a linear, branched or cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons. Alkoxy and lower alkoxy can include methylenedioxy and ethylenedioxy. Representative alkoxy or alkoxyl groups include methoxy and ethoxy.

[0089] Acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched or cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, propionyl, isobutyryl, /-butoxy carbonyl, benzoyl, benzyloxycarbonyl and the like. Lower-acyl refers to groups containing one to four carbons. The double bonded oxygen, when referred to as a substituent itself, is called "oxo". [0090] Aryl and heteroaryl refers to (i) a phenyl group (or benzene) or a monocyclic 5- or 6-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, N, or S; (ii) a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-4 heteroatoms selected from O, N, or S; or (iii) a tricyclic 13- or 14- membered aromatic or heteroaromatic ring system containing 0-5 heteroatoms selected from O, N, or S. The aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole. As used herein aryl can refer to residues in which one or more rings are aromatic, but not all need be. Representative aryl groups include phenyl and naphthyl, such as phenyl. Representative heteroaryl groups include a 5- or -6 membered heteroaromatic ring containing 1-4 (such as 1 or 2, e.g. 1) heteroatoms selected from O, N, or S. Examples of heteroaryl groups include pyridinyl, thiophenyl and furanyl. Particular examples are thiophenyl and furanyl.

[0091] Arylalkyl refers to an alkyl residue attached to an aryl ring. Examples are benzyl, phenethyl and the like. This is in contradistinction to alkylaryl, in which an aryl residue is attached to the parent structure through alkyl (e.g. a p-tolyl residue). Heteroarylalkyl refers to a substituent in which a heteroaryl residue is attached to the parent structure through alkyl. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like. In one embodiment, the alkyl group of an arylalkyl or a heteroarylalkyl is an alkyl group of from 1 to 6 carbons.

[0092] The term "heterocycle" refers to a monocyclic, bicyclic or tricyclic residue with 1 to 13 carbon atoms and 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Unless otherwise specified, a heterocycle may be non-aromatic or aromatic. The heterocycle may be fused to an aromatic hydrocarbon radical. Examples include pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,5-trithianyl, benzo(b)thiophenyl, benzimidazolyl, quinolinyl, and the like. A nitrogen heterocycle is a heterocycle containing at least one nitrogen in the ring; it may contain additional nitrogens, as well as other heteroatoms. Examples include piperidine, piperazine, morpholine, pyrrolidine and thiomorpholine. It is to be noted that heteroaryl is a subset of heterocycle in which the heterocycle is aromatic; examples include pyridine, pyrrole and thiazole. Examples of heterocyclyl residues additionally include piperazinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxo-pyrrolidinyl, 2-oxoazepinyl, azepinyl, A- piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamoφholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, oxadiazolyl, triazolyl and tetrahydroquinolinyl.

[0093] As used herein, the term "optionally substituted" may be used interchangeably with "unsubstituted or substituted". When substituted alkyl, aryl, cycloalkyl, heterocyclyl, etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms (for example, 1 or 2) in each residue are replaced with a specified radical. For example, substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with halogen, alkyl, haloalkyl, haloalkoxy, hydroxy, loweralkoxy (which for the purpose of the present disclosure includes methylene dioxy and ethylene dioxy), oxaalkyl, carboxy, carboalkoxy (also referred to as alkoxycarbonyl[-C(=O)O-alkyl]), carboxamido ([- Q=O)NH₂]), alkylaminocarbonyl [-C(=O)NH-alkyl]), alkoxycarbonylamino [ HNC(=O)O-alkyl], acyl, alkoxyalkyl, benzenesulfonyl, cyano, carbonyl, nitro, amino, hydroxyalkyl, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl (including cycloalkylaminoalkyl), dialkylaminoalkyl, dialkylaminoalkoxy, heterocyclylalkoxy, mercapto, alkylthio, alkylsulfinyl, alkylsulfonyl, acylamino, acylaminoalkyl, acylaminoalkoxy, amidino, alkoxycarbonylamino, acetoxy, sulfoxide, sulfone, sulfonylamino, aryl, phenyl, heterocyclyl, hydroxyimino, alkoxyimino, aminosulfonyl, trityl, amidino, guanidino, ureido, benzyloxyphenyl, benzyl, heteroaryl, heterocyclylalkyl, phenoxy, benzyloxy, or heteroaryloxy. Haloakyl refers to an alkyl group in which one or more hydrogens are replaced by halogen, for example, trifluoromethyl, trifluoromethoxy, trichloroethyl. and difluoromethyl. 'Oxo" is also included among the substituents referred to in "'optionally substituted"; it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g. on phenyl). In one embodiment, 1, 2 or 3 hydrogen atoms are replaced with a specified radical. In another embodiment 1 or 2 hydrogen atoms are replaced with a specified radical. In another embodiment, when substituted, alkyl, aryl, heterocyclyl, etc, may be substituted by 1 or 2 substituents selected from the group consisting Of CpC₄ alkyl (e.g. methyl), Ci-C₄ alkoxy (e.g. methoxy), halogen (e.g. chlorine, fluorine), trifluoromethyl, trifluoromethoxy.

[0094] Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyl and the like. The term oxaalkyl is intended as it is understood in the art, namely, it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds) (Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 1196, but without the restriction of ^fI 27(a), incorporated by reference in its entirety). It does not refer to doubly bonded oxygen, as would be found in carbonyl groups. Similarly, thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons has been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.

[0095] The term "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine. Representative examples of halogen are fluorine and chlorine.

[0096] The terms "haloalkyl" and "haloalkoxy" refers to alkyl or alkoxy, respectively, substituted with one or more halogen atoms. The terms "alkylcarbonyl" and "alkoxycarbonyl" mean -C(=O)alkyl or -C(=O)alkoxy, respectively.

[0097] Substituents Rⁿ are generally defined when introduced and retain that definition throughout the specification.

[0098] It will be recognized that the compounds provided herein can include radiolabeled compounds, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. For example, radioisotopes of hydrogen, carbon, phosphorous, sulfur, and fluorine include ³H, ¹⁴C, ³²P, ³⁵S, and ¹⁸F, respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are envisaged. Tritiated (³H) and carbon- 14 (¹⁴C) radioisotopes are particularly preferred for their ease in preparation and detectability. Radiolabeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent.

[0099] The term "methods of treating or preventing" can refer to amelioration, prevention or relief from the symptoms and/or effects associated with disorders. The term "preventing" as used herein refers to administering a medicament beforehand to forestall or obtund an acute episode or, in the case of a chronic condition, to diminish the likelihood or severity of the condition. It will be understood that the term "prevent" is not an absolute term, and can refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition. As used herein, reference to "treatment" of a patient is intended to include prophylaxis.

[0100] Compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. The configuration of any carbon-carbon double bond appearing herein may be illustrative of particular embodiments, and may not be intended to designate a particular configuration; thus a carbon-carbon double bond depicted arbitrarily herein as trans may be Z, E or a mixture of the two in any proportion.

[0101] The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr J. Chem. Ed. 62, 114-120 (1985), incorporated by reference in its entirety. Accordingly, solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. For example, the following graphic representation:

[0102] can indicate a 50:50 mixture of the following trans enantiomers:

[0103] In another example, the following graphic representation can indicate a single diastereomer of unknown stereochemistry:

[0104] In some embodiments provided herein, diastereomers are named and data is provided; however, it is to be understood that it may not be known which chemical name matches the structural representation.

[0105] In another example, the following graphic representation can indicate a trans relationship between substituents at the 3- and 4-positions in:

[0106] It will be appreciated by one of skill in the art that it is likely that one enantiomer in a racemic mixture may have increased activity. For example, in some embodiments, the S-, S-, R- (or, in the case of R⁴ as a heteroaryl or another substituent that would change the orientation around position 4, S-, S-, S-) configuration may have increased activity, an example includes:

[0107] Nonetheless, mixtures that meet the criterion for activity are provided.

[0108] An individual isomer or diastereoisomer isolated such as to be substantially free of the other isomer or diastereoisomer (i.e. pure) may be isolated such that less than about 10%, particularly less than about 1%, for example less than about 0.1% of the other isomer or diastereoisomer is present.

[0109] The compounds described herein may be in a crystalline or amorphous state. Furthermore, if crystalline, the compounds may exist in one or more polymorphic forms. The most thermodynamically stable polymorphic form, at room temperature, of compounds of formula (I), (Ib) and (II) are of particular interest.

[0110] Polymorphic forms of compounds may be characterized and differentiated using a number of conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD), infrared spectroscopy (IR), Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid state nuclear magnetic resonance (ssNMR).

[0111] The terminology related to "protecting", "deprotecting" and "protected" functionalities is well understood by persons of skill in the art and can be used in the context of processes which involve sequential treatment with a series of reagents. In that context, a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection" occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified a person of ordinary skill can readily envision those groups that would be suitable as "protecting groups".

[0112] The abbreviations Me, Et, Ph, Tf, Ts and Ms represent methyl, ethyl, phenyl, trifiuoromethanesulfonyl, toluenesulfonyl and methanesulfonyl, respectively. A comprehensive list of abbreviations appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled "Standard List of Abbreviations," is incorporated herein by reference in its entirety.

[0113] While it may be possible for the mixtures and compounds of the invention to be administered as the raw chemical, it is possible to present them as a pharmaceutical composition. According to a further aspect, a pharmaceutical composition comprising formula I, formula Ib, formula II, pharmaceutically acceptable salts, and/or mixtures thereof, and one or more pharmaceutically acceptable carriers thereof are provided. In some embodiments, compositions may further comprise one or more additional therapeutic ingredients. The carrier(s) can be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Furthermore, when reference is made to a compound or a pharmaceutically acceptable salt thereof, it will be understood that claims which depend from that independent claim which refer to such a compound also include pharmaceutically acceptable salts of the compound, even if explicit reference is not made to the salts in the dependent claim.

[0114] Compositions are provided suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The most suitable route may depend upon the condition and disorder of the recipient. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Some methods include the step of bringing into association an active ingredient, for example, formula I, formula Ib, formula II, pharmaceutically acceptable salts, solvates and/or mixtures thereof, and a pharmaceutically acceptable carrier, which may constitute one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association an active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired compositions.

[0115] Compositions provided herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of an active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

[0116] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.

[0117] Compositions may include a "pharmaceutically acceptable inert carrier." A pharmaceutically acceptable inert carrier can include one or more inert excipients, for example, starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents, and the like. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or non-aqueous techniques. Pharmaceutically acceptable carriers may also include controlled release means well known in the art.

[0118] Compositions and formulations provided herein may optionally include additional ingredients for example, therapeutic ingredients, anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, and the like. Any such optional ingredient can be compatible with compounds provided herein to insure the stability of the formulation.

[0119] The dose range for adult humans is generally from 0.005 mg to 10 g/day orally. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. The precise amount of compound administered to a patient can be determined by an attendant physician. However, the dose employed will depend on a number of factors, including, for example, the age, sex, and weight of the patient, the precise disorder to be treated, and the severity of the disorder.

[0120] As used herein, and as would be understood by the person of skill in the art, the recitation of "a compound" can include salts, solvates and inclusion complexes of that compound. Thus, for example, the recitation "a compound of formula II" as depicted above would include salts in which -NR³ is NH⁺ M^", wherein M is any suitable counterion.

[0121] Additionally, some structures depicted herein can include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures provided herein except, for example, for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C- enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0122] Compounds or salts thereof provided herein may exist in solvated form. The term "solvate" can refer to formula I, formula Ib, formula II, and/or mixtures thereof in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate. Inclusion complexes are described in Remington: The Science and Practice of Pharmacy 19^th Ed. (1995) volume 1 , page 176-177, which is incorporated herein by reference in its entirety. The most commonly employed inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic.

[0123] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. When the compounds of the present invention are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, carbonic, citric, ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, fumaric, glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, pamoic, pantothenic, phosphoric, polygalacturonic, salicylic, stearic, succinic, sulfuric, tannic, tartaric acid, teoclatic, p-toluenesulfonic, and the like. When the compounds contain an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.

[0124] Compounds provided herein of formula I, formula Ib, formula II, and/or mixtures thereof are modulators of sst₄. Such compounds have utility in treating and preventing pain and inflammatory conditions, as well as other disorders such as, but not necessarily limited to, Alzheimer's disease and psychiatric disorders. Examples of pain that may be treated with compounds provided herein include nociception. More examples of pain that may be treated with compounds provided herein conditions include osteoarthritis, acute gout, inflammatory arthropathy, dysmenorrhoea, endometriosis, headache, migraine, postoperative pain, back pain, sciatica, sprains, strains, rheumatism, dental pain, kidney stones and fever. Examples of inflammatory confditions that can be treated with compounds provided herein include airway inflammatory conditions. Examples of airway inflammatory conditions include asthma, chronic obstructive pulmonary disesase

[0125] Pyrrolidine carboxamides provided herein are agonists for the sst₄ receptor. Somatostatins SRIF- 14 and SRIF-28, which contain 14 and 28 amino acids respectively, are two key members of the somatostatin peptide family and bind to the five somatostatin (sst) receptors with nanomolar affinity (Weckbecker et al, Nature Reviews Drug Discovery, 2003, 2, 999-1017; Pinter et al, Pharmacology & Therapeutics, 2006, 112, 440-456, incorporated by reference in its entirety).

[0126] It is presumed that inhibition of nociceptive and inflammatory processes is mediated via SSt₄ (Szolcsanyi et al., Br. J. of Pharmacol, 1998, 125, 916- 922; Szolcsanyi et al, Br. J. of Pharmacol, 1998, 123, 936-942; Helyes et al, Br. J. of Pharmacol, 2006, 149, 405-415, incorporated by reference in its entirety). Antinociceptive and anti-inflammatory effects have been demonstrated in a variety of rodent animal models with a selective small molecule sst₄ agonist, J-2156 (Sandor et al , Eur. J. Pharmacol, 2006, 539, 71-75; Helyes et al, Arthritis Rheum., 2004, 50, 1677-1685, incorporated by reference in its entirety). Accordingly, compounds provided herein can be used to treat such conditions.

[0127] In light of the strong evidence that links sst₄ to pain and inflammation, a SSt₄ sub-type selective small molecule agonist will be a useful therapeutic agent for treatment of various pain and inflammatory conditions. A selective modulator will prevent or minimize the potential endocrine side effects mediated through other receptor sub-types.

[0128] Centrally acting sst₄ agonists would also be of great potential for treating several human pathologies. It has been shown that the SRIF level and sst₄ expression level are altered in patients with Alzheimer's disease (AD), temporal lobe epilepsy, Parkinson's disease and cortical injury (Crider and Witt, Mini-Reviews in Med. Chem., 2007, 7, 213-20 and references therein, incorporated by reference in its entirety). In addition, a selective sst4 small molecule agonist, L-803,087, was shown to enhance the endozepine release in cultured rat astrocytes, and in turn linked the sst₄ agonism as a potential approach for treatment of certain neuropsychiatric disorders (Crider and Witt, Mini-Reviews in Med. Chem., 2007, 7, 213-20 and references therein, incorporated by reference in its entirety). Thus, centrally acting sst₄ modulators may bring benefits to these disease conditions.

[0129] One aspect of the invention relates to a mixture of isomers or a mixture of compounds wherein at least 51 % of said mixture contains the 3S configuration of the pyrrolidine, falling within the genus described by formula I:

[0130] another aspect of the invention relates to a racemic mixture of the isomers of formula Ib:

Ib.

[0131] R¹ and R² are each independently selected from hydrogen and (Ci-C₆) alkyl or together, R¹ and R² form a (C₃-C₆) cycloalkyl; R³ is selected from hydrogen and (Ci-C₆) alkyl; R⁴ and R⁵ are each selected from optionally substituted heterocyclyl and optionally substituted aryl; R⁴ and R⁵ are each selected from heterocyclyl and aryl each optionally substituted with one or more of hydrogen, trifluoromethyl, halogen, (C]-C₆) alkyl, (Ci-C₆) alkyoxy, cyano and trifluoromethoxy. Certain substituents in certain positions of the R⁴ and R⁵ aryls and heteroaryls may lead to a decrease in activity.

[0132] In some embodiments, R³ is hydrogen and R⁴ and R⁵ are each selected from optionally substituted phenyl. In some embodiments, R⁴ is a phenyl substituted with one or more of hydrogen, fluorine or methoxy. In some embodiments, R⁵ is a phenyl substituted with one or more of hydrogen, trifluoromethyl, chlorine, methoxy or fluorine. In some embodiments, R⁴ is optionally substituted naphthyl or thiophene. In some embodiments, R⁵ is optionally substituted naphthyl, pyrindinyl or indolyl.

[0133] In some embodiments, R¹ is methyl or ethyl and R² is hydrogen, and the R¹ -bearing carbon is in the S configuration. In some embodiments, R¹ and R² are both hydrogen, are both methyl or, together, R¹ and R² are cyclopropyl.

[0134] In some embodiments, compounds include formula II in which the configuration of the pyrrolidine ring is 3S:

[0135] R¹ and R² are each independently selected from the group consisting of hydrogen and (Ci-C₆) alkyl or together, R¹ and R² form a (C₃-C₆) cycloalkyl. R³ is selected from hydrogen and (Ci-C₆) alkyl. R⁴ is selected from a group consisting of optionally substituted heterocyclyl and optionally substituted aryl. R⁵ is chosen from a group consisting of optionally substituted heterocyclyl and optionally substituted aryl. Y is a direct bond or -CH₂ or together, Y and R¹ can form a cyclopropane. The structural activity relationship developed thus far indicates that certain combinations of Y and R or R⁵, as well as the presence of substituents in certain positions of the R⁴ and R⁵ aryls and heteroaryls, may lead to a decrease in activity. In some embodiments, when R⁵ is pyridinyl or pyrimidinyl, R¹ must be (C ₁-C₆) alkyl, and when Y is a direct bond, R⁵ is not /?αrα-methoxyphenyl or/?αrα-chlorophenyl.

[0136] In some embodiments, R³ is hydrogen. In some embodiments, R³ is methyl or ethyl. In some embodiments, Y is a direct bond. In some embodiments, Y is a direct bond, R¹ is methyl or ethyl, R² is hydrogen, and the R¹ -bearing carbon is in the S configuration. In some embodiments, Y can be -CH₂ or Y and R¹ together can form a cyclopropane.

[0137] In some embodiments, R⁴ and R⁵ are each optionally substituted aryl. In some embodiments, R⁴ and R⁵ are each phenyl optionally substituted with one or more of hydrogen, trifluoromethyl, halogen, (Ci-C₆) alkyl, (C]-C₆) alkyloxy, cyano or trifiuoromethoxy. In some embodiments, R⁴ is a phenyl substituted with one or more of hydrogen, trifluoromethyl, chloro, fluoro, methyl, ethyl, methoxy, ethoxy, cyano or trifiuoromethoxy. In some embodiments, R⁴ can be napthyl or thiophene. In some embodiments, R⁵ is a phenyl substituted with one or more of hydrogen, chloro, fluoro, methyl, ethyl, methoxy or ethoxy. In some embodiments, R³ can be optionally substituted napthyl, pyrindin-2-yl, pyrindin-3-yl or indole.

[0138] In some embodiments, R³ is hydrogen; R¹ is methyl or ethyl; R² is hydrogen; Y is a direct bond; R⁴ is a phenyl substituted with one or more of hydrogen, trifluoromethyl, chloro, fluoro, methyl, ethyl, methoxy, ethoxy, cyano or trifiuoromethoxy; and R⁵ is a phenyl substituted with one or more of hydrogen, chloro, fluoro, methyl, ethyl, methoxy or ethoxy.

[0139] In one embodiment, R⁴ is aryl or heteroaryl each optionally substituted by 1 or 2 substituents independently selected from the group consisting of Ci-C₄ alkyl (e.g. methyl), Cj-C₄ alkoxy (e.g. methoxy), halogen (e.g. chlorine, fluorine), trifluoromethyl and trifluoromethoxy. In another embodiment R⁴ is unsubstituted aryl or unsubstituted heteroaryl.

[0140] In one embodiment R⁴ is optionally substituted phenyl or naphthyl. In another embodiment R⁴ is phenyl optionally substituted in the para position. In another embodiment R⁴ is unsubstituted phenyl or naphthyl.

[0141] In one embodiment R⁴ is optionally substituted pyridinyl, thiophenyl or furanyl.

[0142] In one embodiment, R⁵ is aryl or heteroaryl each optionally substituted by 1 or 2 substituents independently selected from the group consisting of CpC₄ alkyl (e.g. methyl), Ci-C₄ alkoxy (e.g. methoxy), halogen (e.g. chlorine, fluorine), trifluoromethyl and trifluoromethoxy. In another embodiment R⁵ is unsubstituted aryl or unsubstituted heteroaryl.

[0143] In one embodiment R⁵ is optionally substituted phenyl. In another embodiment R⁵ is phenyl optionally substituted in the ortho or meta positions. In another embodiment R⁵ is unsubstituted phenyl.

[0144] In one embodiment R⁵ is optionally substituted pyridinyl, thiophenyl or furanyl.

[0145] In one embodiment Y is CH₂ In another embodiment Y is a direct bond.

[0146] In one embodiment R¹ and R² are each independently selected from hydrogen or Ci to C₃ alkyl or R¹ and R² together form cyclopropyl.

[0147] In one embodiment R³ is hydrogen or methyl.

[0148] In another embodiment there is provided a compound or mixture of compounds (or salts thereof) selected from the compounds of the Examples.

[0149] In one embodiment,there is provided a compound (3S,4/?)-4-(4- chlorophenyl)-N-((iS)-l-phenylethyl)pyrrolidine-3-carboxamide or a salt thereof.

[0150] In one embodiment there is provided a compound (3S,4R)-N-((S)-\- phenylethyl)-4-(4-(trifluoromethyl)phenyl)pyπOlidine-3-carboxamide, or salt thereof.

[0151] In one embodiment there is provided a compound (3S,4R)-N-((S)-\-(3- methoxyphenyl)ethyl)-4-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxamide, or salt thereof.

[0152] In one embodiment there is provided a compound (3S,4R)-4-(4- chlorophenyl)-jV-((5)-l-(pyridin-3-yl)ethyl)pyrrolidine-3-carboxamide, or salt thereof. [0153] In one embodiment, there is provided a compound (3S,4R)-N-((S)-\-(6- methoxypyridin-2-yl)ethyl)-4-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxamide, or salt thereof.

[0154J In one embodiment, there is provided a compound (3S,4R)-4-(3,4- dichlorophenyl)-N-((S)-l-(3-methoxyphenyl)ethyl)pyrrolidine-3-carboxamide, or salt thereof.

[0155] In one embodiment, there is provided a compound (3S,4R)-N-((S)-1- m-tolylethyl)-4-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxamide, or salt thereof.

[0156] In one embodiment, there is provided a compound (3S,4R)-4-(4- ethylphenyl)-N-((S)-l-(3-methoxyphenyl)ethyl)pyrrolidine-3-carboxamide, or salt thereof.

[0157] In one embodiment, there is provided a compound (3S,4R)-N-((S)-1- phenylethyl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidine-3-carboxamide, or salt thereof.

[0158] In one embodiment, there is provided a compound (3S,4S)-N-((S)-1- phenylethyl)-4-(5-(trifluoromethyl)furan-2-yl)pyrrolidine-3-carboxamide, or salt thereof.

[0159] In one embodiment, there is provided a compound (3S,4R)-N-((S)-1 - (3-methoxyphenyl)ethyl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidine-3-carboxamide, or salt thereof.

[0160] In one embodiment, there is provided a compound (3S,4S)-4-(5- chlorothiophen-2-yl)-N-((S)-l-(3-methoxyphenyl)ethyl)pyrrolidine-3-carboxamide, or salt thereof.

[0161] In one embodiment, there is provided a compound (3S,4S)-N-((S)-1- (3-methoxyphenyl)ethyl)-4-(5-(trifluoromethyl)furan-2-yl)pyrrolidine-3-carboxamide, or salt thereof.

[0162] In one embodiment, there is provided a compound (3S,4S)-4-(5- chlorofuran-2-yl)-N-((S)-l-(3-methoxyphenyl)ethyl)pyrrolidine-3-carboxamide, or salt thereof.

[0163] In one embodiment salts are pharmaceutically acceptable salts.

[0164] In another embodiment compounds are in the form of the free base.

[0165] It will be appreciated that the present invention extends to combinations of substituents, representative groups and embodiments as defined above.

[0166] Some embodiments of the present invention relate to methods of treating or preventing disorders dependent upon the modulation of SSt₄. Some methods include administering compounds, mixtures or compositionsprovided herein to a subject in need of such treatment. Some embodiments relate to disclosed compounds or mixtures for use in therapy, for the prevention or treatment of pain, inflammatory conditions, Alzheimer's disease, temporal lobe epilepsy, Parkinson's disease, cortical injury and psychiatric disorders comprising administering compounds, mixtures or compositions of the invention to a subject in need of such treatment.

[0167] Some embodiments of the present invention relate to compositions and formulations comprising formula I, formula Ib, formula II, and/or mixtures thereof, and a pharmaceutically acceptable carrier. The compositions may be administered alone or in combination with another agent, drug, or hormone, and may be administered by any number of acceptable routes. Compositions suitable for the use can include compositions wherein the active ingredients are contained in an effective amount to achieve the intended purpose. The determination of an effective dose is well within the capability of those skilled in the art.

[0168] Abbreviations: The following abbreviations and terms have the indicated meaning throughout, unless otherwise stated:

AcOH Acetic acid

ACE-Cl 1-Chloroethyl chloroformate

AD Alzheimer's disease

Bn Benzyl

Boc t-butyloxy carbonyl

BSA Bovine serum albumin

C Carbon

CDCl₃ Deuterated chloroform

CD₃OD Deuterated methanol

(CD₃)₂SO Deuterated dimethyl sulfoxide

CHO Chinese hamster ovary (cells)

DCM dichloromethane = methylene chloride = CH₂Cl₂ δ NMR chemical shift referenced to tetramethylsilane

DMA iV.jV-dimethylacetamide

DMF N,N-dimethylformamide

DMSO Dimethyl sulfoxide

EC₅o concentration of a drug that produces 50% effect

EDC N-(3-dimethylaminopropyl)-Λ^-ethylcarbodiirnide

EDTA ethylenediaminetetraacetic acid

Et Ethyl

Et₃N Triethylamine

EtOAc Ethyl acetate

ESI Electrospray ionization

GDP guanosine diphosphate

GPCR G protein-coupled receptor GTP guanosine triphosphate

¹H NMR Proton Nuclear Magnetic Resonance h hours

HDMS 1,1,1 ,3,3,3-hexamethyldisilazane

HOBt hydroxybenzotriazole i iso

/Pr₂Net Diisopropylethylamine m meta

Me Methyl

MeOH methanol = CH₃OH

MHz Megahertz min minutes

Ms methanesulfonyl

N nitrogen n-BuLi n-Butyl lithium

NMR Nuclear Magnetic Resonance

P- para

Ph Phenyl r.t. room temperature sat. saturated

SPA Scintillation Proximity Assay

SRIF somatotropin release inhibiting factors

Tf trifluoromethanesulfonyl

TFA trifluoro acetic acid

THF tetrahydrofuran

TMS trimethylsilyl

Ts toluenesulfonyl

WGA wheat germ agglutinin

Synthesis of trans-3,4-disubstituted pyrrolidine derivatives

[0169] Compounds of formula I and II can be synthesized by means of conventional organic synthesis executable by one skilled in the art. Examples of methods to synthesize compounds of formula I and II are provided in general reaction Schemes 1-5 and in Procedures A-L.

[0170] Generation of substituted methyl /røm'-cinnamates IV can be achieved utilizing methyl (triphenylphosphoranylidene)acetate (III) and a substituted carboxaldehyde II. Acid catalysed [3 + 2] cyclization of IV with trimethylsilyl(methoxymethyl)benzylamine (V) provides the racemic trarø-substituted pyrrolidine derivative VI, which can be hydrolysed to carboxylic acid VII. Amide coupling of a primary amine with intermediate VII, followed by debenzylation, provides compounds of formula I (Scheme 1). [0171] Compound II can be replaced with a substituted or unsubstituted heteroaryl carboxaldehyde to generate intermediates IV, VI, VII and VIII. These intermediates can be used in the subsequent syntheses to yield products containing a heteroaryl moiety. Scheme 1

Hydrolysis

Procedure A: (ip-Methyl 3-(4-(trifluoromethyl)phenyl)acrylate (2)

1 2

[0172] To a stirred solution of methyl(triphenylphosphoranylidine)acetate (350.0 g, 1.05 mol; Aldrich, MO, USA) in CH₂Cl₂ (1 L) was added 4- trifluoromethylbenzaldehyde (1) (175.0 g, 1 mol; Aldrich, MO, USA) and the resultant mixture was stirred at room temperature for 8 h. The solvent was removed by evaporation in vacuo and the resulting oil was purified by flash column chromatography (SiO₂; elution with 10: 1 petroleum ether/EtOAc) to afford the (£)-methyl 3-(4- (trifiuoromethyl)phenyl)acrylate (2) as yellow solid (185 g, 80 % yield).

[0173] Data for (£)-methyl 3-(4-(trifluoromethyl)phenyl)acrylate (2): ¹H NMR (400 MHz, CDCl₃) δ 7.85-7.60 (m, 5H), 6.54 (d, I H), 3.85 (s, 3H). Procedure B: (+/-)-tr cms-Methyl l-benzyl-4-(4-(trifluoromethyl)phenyl)pyrrolidine-3- carboxylate (3)

2 (+/-)-3

[0174] To a stirred solution of (£)-methyl 3-(4-

(trifluoromethyl)phenyl)acrylate (2) (185 g, 0.8 mol) in CH₂Cl₂ (1 L) was added N- (methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (200 g, 0.8 mol; Aldrich, MO, USA). The resulting mixture was cooled to 0 ⁰C and a solution of TFA (0.5 mL, 0.1 eq) in CH₂Cl₂ (30 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The solvent was removed by evaporation in vacuo and the resulting oil was purified by flash column chromatography (SiO₂; elution with 1 :5 EtOAc/hexanes) to give (+/-)-tr<ms-methyl 1 -benzyl-4-(4-

(trifluoromethyl)phenyl)pyrrolidine-3-carboxylate (3) (152 g, 80 % yield).

[0175] Data for (+/-)-trans-methyl l-benzyl-4-(4-

(trifluoromethyl)phenyl)pyrrolidine-3-carboxylate (3): ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.08 (m, 9H), 3.60-3.48 (m, 3H, partial overlap with singlet at 3.52), 3.52 (s, 3H), 3.02-2.89 (m, 2H), 2.85-2.79 (m, IH), 2.73-2.62 (m, 2H).

[0176] Alternatively, protecting group exchange of compound VI involving debenzylation of the pyrrolidine nitrogen followed by Boc protection provides intermediate X, which can be hydrolyzed to the Boc-protected pyrrolidine carboxylic acid XI (Scheme 2). Amide coupling of a primary amine with intermediate XI, followed by Boc deprotection, provides compounds of formula I.

Scheme 2

Hydrolysis

Procedure CJh (+/-)-trans-\-tert-Bu\y\-3-methy\ 4-(4-

(trifluoromethyl)phenvDpyrrolidine- 1 ,3-dicarboxylate (4)

(+/-)-3 (⁺/-)-4

[0177] To a solution of (+/-)-3 (55.0 g, 152 mmol) in MeOH (1200 mL) was added triethylamine (83.5 g, 827 mmol), 10% Pd/C (15.0 g) and BoC₂O (99.0 g, 455 mmol), and the reaction mixture was then stirred under H₂ (1 atm) at 50 ⁰C for 16 h. After cooling to room temperature, the mixture was filtered through a pad of Celite ' rinsing with MeOH. The filtrate was concentrated in vacuo and the residue was partitioned between EtOAc and aqueous HCl (pH ~5). The organic phase was washed with brine, dried (Na₂SO₄), filtered and concentrated, in vacuo. The crude product was purified by flash column chromatography (SiO₂; elution with 30:1 EtOAc/hexane) to give (+/-)-trans-l-tert-buty\ 3-methyl 4-(4-(trifluoromethyl)phenyl)pyrrolidine-l ,3- dicarboxylate (4) as a yellow oil (50.0 g, 88% yield).

[0178] Data for (+/-)-trans-l-tert-buty\ 3-methyl 4-(4-

(trifluoromethyl)phenyl)pyrrolidine-l,3-dicarboxylate (4): ¹H NMR (400 MHz, CDCl₃, mixture of Boc rotational isomers) δ 7.62 (m, 2H), 7.41 (m, 2H), 4.10-3.80 (m, 2H), 3.80- 3.60 (m, 6H), 3.45 (m, IH), 1.66 (s, 9H).

Procedure C2j (+l-)-trans- 1 -fert-Butyl-3-methyl 4-(4-

(trifluoromethyl)pheny0pyrrolidine-h3-dicarboxylate (4)

[0179] Compound (+/-)-4 can also be prepared by using palladium hydroxide catalyst for the debenzylation step. rC

(+/-)-3 (+!-)^■*

[0180] To a solution of (+/-)-3 (152.0 g, 0.42 mol) in MeOH (1200 mL) was added 20% Pd(OH)₂/C (10.0 g). The reaction was kept under H₂ (50 psi) for 8 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give a solid (98 g). The solid was dissolved in MeOH (0.5 L) with triethylamine (20 mL) and BoC₂O (120.0 g, 0.55 mol). The reaction was stirred at rt for 4 h. The solvent was evaportaed to give (+/- )-trans-\-tert-b\xty\ 3-methyl 4-(4-(trifluoromethyl)phenyl)pyrrolidine-l,3-dicarboxylate (4) as a yellow oil (148.0 g, 94 % yield from (+/-)-3).

Procedure D; (+l-)-trans- 1 -(fert-Butoxycarbonyl)-4-(4-(trifluoromethyl)- phenyl)pyrrolidine-3-carboxylic acid (5)

(+/-M (^+/-)-5

[0181] A mixture of (+/-)-4 (148.0 g, 0.40 mol) and LiOH (40 g, 1 mol) in MeOH (300 mL) and H₂O (200 mL) was stirred at rt for 4 h. MeOH was removed under in vacuo, and the aqueous was acidified with 2M aqueous HCl to pH=3. The precipitate was collected by filtration, washed with H₂O and dried to give {+l-)-trans-\-(tert- butoxycarbonyl)-4-(4-(trifluoromethyl)-phenyl)pyrrolidine-3-carboxylic acid 5 (135 g, 94% yield).

[0182] Data for (+/-)-trαra-l-(/er/-butoxycarbonyl)-4-(4-(trifluoromethyl)- phenyl)pyrrolidine-3-carboxylic acid (5): ¹H NMR (400 MHz, d6-OMSO) δ 12.57 (br s, IH), 7.69 (d, IH), 7.58 (d, IH), 3.75 (m, 2H), 3.63 (m, IH), 3.48-3.22 (m, 3H, partially obscured by H₂O peak), 2.81 (d, 3H). Procedure El : (+/-)-trans-tert-Buty\ 3-((3-methoxybenzyl)carbamoyl)-4-(4- chlorophenvDpyrrolidine-l -carboxylate (7)

(+/-)-6 (+/-J-7

[0183] To a suspension of (+/-)-trαrø-4-(4-chlorophenyl) pyrrolidine-3- carboxylic acid (6) (100 mg, 0.31 mmol), EDC (71 mg, 0.37 mmol) and HOBt monohydrate (56 mg, 0.37 mmol) in CH₂Cl₂ (2 ml) was added 3-methoxybenzylamine (60 μL, 0.46 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with methylene chloride (3 mL) and washed with sat. sodium carbonate solution (1 X 3 mL) followed by 1 M HCl (1 X 3 mL). The organic phase was dried (Na₂SO₄) and the solvent removed in vacuo to provide trans-(+/-)-tert -butyl 3-((3- methoxybenzyl)carbamoyl)-4-(4-chlorophenyl)pyrrolidine-l -carboxylate (7) (1 17 mg, 85%).

[0184] Data for (+/-)-trans-tert -butyl 3-((3-methoxybenzyl)carbamoyl}-4-(4- chlorophenyl)pyrrolidine-l -carboxylate (7): MS (ESI) m/z: 445.3 [M+H]⁺ Procedure E2: (+/-)-/rαn5-N-(3-Methoxybenzyl)-4-(4-chlorophenyl)pyrrolidine-3- carboxamide (Example 71)

(^+/-)-7 Example 71

[0185] To a solution of trans-{+l-)-tert -butyl 3-((3- methoxybenzyl)carbamoyl)-4-(4-chlorophenyl)pyrrolidine-l -carboxylate (7) (25 mg, 0.056 mmol) in CH₂Cl₂ (1 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was removed in vacuo and the residue purified by semi-prep, hplc to provide (+/-)-tra«5-iV-(3-methoxybenzyl)-4-(4- chlorophenyl)pyrrolidine-3-carboxamide (Example 71) as a TFA salt (21 mg, 82%).

[0186] Data for (+/-)-/rora-N-(3-methoxybenzyl)-4-(4- chlorophenyl)pyrrolidine-3-carboxamide (Example 71): ¹H NMR (400 MHz, CD₃OD) δ 7.35 (d, 2H), 7.29 (d, 2H), 7.14 (t, IH), 6.78 (dd, IH), 6.62 (t, IH), 6.57 (d, IH), 4.44 (d, IH), 4.09 (d, IH), 3.79-3.63 (m, 3H, overlap with peak at 3.74), 3.74 (s, 3H), 3.57 (dd, IH), 3.38 (t, IH), 3.21 (q, IH); MS (ESI) m/z: 345.3 [M+H]⁺

[0187] Analogous compounds of formula I can be synthesized using similar experimental procedures to those described above.

[0188] Coupling of the carboxylic acid intermediate XI with a chiral primary amine of defined stereochemistry (* RNH₂) provides diastereomeric amides XIIa and XIIb (Scheme 3). In some instances, diastereomers XIIa and XIIb can be separated by standard chromatographic or crystallographic methods, and subsequent Boc deprotection of compound XIIa and/or compound XIIb provides compounds of formula I as the corresponding pure enantiomer(s) (Ia and/or Ib). Scheme 3

De-Boc De-Boc

Procedure F: (3SAR)-tert-Butγl 3-(((.SVl-phenylethyl)carbamoyl)-4-(4-chlorophenyl) pyrrolidine- 1-carboxylate (8a)

(+/-)-6 8a 8b

[0189] To a suspension of (±)-/r<ms-4-(4-chlorophenyl) pyrrolidine-3- carboxylic acid 6 (3.00 g, 9.21 mmol), EDC (2.12 g, 1 1.05 mmol) and HOBt monohydrate (1.69 g, 11.05 mmol) in CH₂Cl₂ (40 mL) was added (1.53 mL, 12.0 mmol) of (5)-α-methyl benzylamine (Aldrich, MO, USA). The reaction mixture was stirred at room temperature for 20 h. The mixture was diluted with CH₂Cl₂ (80 mL) and washed with sat. sodium carbonate solution (1 X 40 niL) followed by 1 M HCl (1 X 40 mL). The organic phase was dried (Na₂SO₄) and the solvent removed in vacuo. The resulting diastereoisomers were separated by flash column chromatography eluting with a linear gradient of 20-40% EtOAc/hexanes over 15 min to provide the preferred (less polar) diastereomer, (3S,4R)-tert-buty\ 3-(((S)- 1 -phenylethyl)carbamoyl>4-(4- chlorophenyl)pyrrolidine-l-carboxylate (8a) (1.9 g, 48%) as a white foam. Procedure G: (3£4/?)-4-(4-ChlorophenvD-N-((,S')- 1 -phenylethyl)pyrrolidine-3- carboxamide (Example 2)

Example 2

[0190] To a solution of (3S,4R)-tert-butyl 3-(((S)-l-phenylethyl) carbamoyl)- 4-(4-chlorophenyl)pyrrolidine-l-carboxylate (8a) (1.90 g, 4.43 mmol) in 1 ,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature for 90 min and the solvent removed in vacuo. The residue was crystallized from acetonitrile to provide HCl salt of (3S',4i?)-4-(4-chlorophenyl)-N-((5)-l- phenylethyl)pyrrolidine-3-carboxamide hydrochloride (Example 2) (1.48 g, 92%) as a white crystalline solid.

[0191] Data for (35,4i?)-4-(4-chlorophenyl)-N-((5)-l-phenylethyl)pyrrolidine- 3-carboxamide hydrochloride (Example 2): ¹H NMR (400 MHz, CD₃OD) δ 7.43 (d, 2H), 7.35 (d, 2H), 7.32-7.20 (m, 5H), 4.94 (m, I H, partial overlap with H₂O peak), 3.77-3.63 (m, 3H), 3.52-3.35 (m, 2H, partial overlap with solvent peak), 3.18 (q, IH), 1.27 (d, 3H); MS (ESI) m/z: 329.4 + 331.4 [M+H]⁺.

[0192] Analogous compounds of formula Ia and/or Ib can be synthesized using similar experimental procedures to those described above. The (5)-α-methyl benzylamine can be replaced with other chiral amines in Procedure F. The corresponding diastereomers resulted form this coupling reaction can be separated accordingly by chromatography. The α-substituted chiral amines can be prepared from asymmetric synthesis or purchased from commercial sources. Asymmetric syntheses of D -substituted chiral amines are well-known in are. For example, the (S)-l-(2-pyridyl)ethylamine used for Example 10 can be prepared according to a literature procedure (J. Am. Chem. Soc. 1973, 95, 81 1). For another example, the (S)-l-(5-chlorofuran-2-yl)ethanamine used in Example 120 can be prepared according to the procedure (Tetrahedron Letters 1999, 40, 6709). It is well known that these types of amine can be prepared by more than one method

(0193] Alternatively, preparation of substituted /rαrcs-cinnamides (XIV) can be achieved by coupling of a primary amine (RNH₂) with a substituted trans-cinnamic acid (XIII) using an appropriate amide coupling reagent, such as EDC, for example. Acid catalyzed [3 + 2] cyclization of IV with trimethylsilyl(methoxymethyl)benzylamine (V) provides racemic trαns-pyπolidine intermediate XV. Removal of the benzyl group, by means of suitable debenzylation conditions provides compounds of formula I (Scheme

4).

[0194] Compound XIII can be replaced with a substituted or unsubstituted heteroarylacrylic acid to generate intermediates XIV and XV. These intermediates can be used in the subsequent syntheses to yield products containing a heteroaryl moiety. Scheme 4

[0195] Coupling of a chiral primary amine of defined stereochemistry (* RNH₂) with a substituted trαns-cixuiamic acid (XIII) followed by acid catalyzed [3 + 2] cyclization of intermediate XIV with trimethylsilyl(methoxymethyl)benzylamine (V) provides diastereomeric trαns-pyπolidines XVa and XVb. In some cases these can be separated by standard chromatographic or crystallographic methods, and then subsequent debenzylation of intermediate XVa and/or XVb provides compounds of formula I as the corresponding pure enantiomer(s) (Ia and/or Ib) (Scheme 5). Scheme 5

Debenzylation Debenzylation

Procedure H: CSVN-Q -PhenylethyDcinnamamide (10)

[0196] To a suspension of cinnamic acid (9) (1.00 g, 6.76 mmol), EDC (1.56 g, 8.10 mmol) and of HOBt monohydrate (1.24 g, 8.10 mmol) in CH₂Cl₂ (30 mL) was added (5)-α-methyl benzylamine (1.13 mL, 8.78 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with CH₂Cl₂ (30 mL) and washed with sat. sodium carbonate solution (1 X 30 mL) followed by 1 M HCl (1 X 30 mL). The organic phase was dried (Na₂SO₄) and the solvent removed in vacuo to provide (S)-N-(I - phenylethyl)cinnamamide (10) (1.61 g, 95%) as a white solid.

[0197] Data for (S)-N-(I -phenylethyl)cinnamamide (10): ¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, IH), 7.38 (m, 2H), 7.27-7.22 (m, 7H), 7.17 (m, IH), 6.28 (d, IH), 5.74 (br d, IH, -NH), 5.18 (m, 1Η), 1.46 (d, 3Η).

Procedure I: (35',4i?)-l-Benzyl-4-phenyl-N-((5)-l-phenylethyl)pyrrolidine-3-carboxamide (Ha) and (3^,45^-1 -benzyl-4-phenyl-N-((.Sl-l-phenylethyl)pyrrolidine-3-carboxamide (lib)

[0198] To a suspension of of (S)-N-(I -phenylethyl)cinnamamide (10) (0.40 g, 1.59 mmol) in anhydrous toluene (7 mL) at 0 °C was added N-benzyl-N- (methoxymethyl)trimethylsilyl methylamine (0.49 mL, 1.90 mmol). The mixture was stirred at 0 °C for 10 mins and a solution of trifluoroacetic acid (30 μL, 0.40 mmol) in methylene chloride (2 mL) was then added. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with EtOAc (20 mL) and washed with sat. sodium carbonate (1 X 10 mL). The organic phase was dried (Na₂SO₄) and the solvent removed in vacuo. The resulting diastereoisomers were separated by flash column chromatography, eluting with a linear gradient of 20-50% EtOAc/hexanes over 15 min to provide the less polar (first eluting) diastereomer (35",4/?)-l-benzyl-4-phenyl-N- ((S)-l-phenylethyl)pyrrolidine-3-carboxamide (lla) (0.38 g, 62%) as a white crystalline solid, and the more polar (second eluting) diastereomer (3i?,45)-l-benzyl-4-phenyl-N- ((5)-l-phenylethyl)pyrrolidine-3-carboxamide (lib) (0.18 g, 30%) as a white crystalline solid. The absolute stereochemistry of lla was determined by single crystal X-ray diffraction.

[0199] Data for (35',4_J??)-l-benzyl-4-phenyl-N-((5)-l-phenylethyl)pyrrolidine-

3-carboxamide (lla): ¹H NMR (400 MHz, CDCl₃) 5 7.36-7.19 (m, 15 H, partial overlap with solvent peak), 6.52 (br d, 1 H, -NH), 5.06 (m, IH), 3.70 (ABq, 2H), 3.50 (m, IH), 3.23 (t, IH), 3.05 (dd, IH), 2.87-2.78 (m, 2H), 2.63 (dd, IH), 1.40 (d, 3H).

[0200] Data for (3#,4S>l-benzyl-4-ρhenyl-ΛH(>S)-l-phenylethyl)pyrrolidine- 3-carboxamide (lib): ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.13 (m, 15 H, partial overlap with solvent peak), 6.51 (br d, 1 H, -NH), 5.05 (m, 1Η), 3.70 (ABq, 2Η), 3.51 (m, IH), 3.26 (t, IH), 3.04 (dd, IH), 2.88-2.79 (m, 2H), 2.65 (app t, IH), 1.43 (d, 3H). Single X-ray diffraction data for compound lla

[0201] The stereochemistry of crystalline material obtained for compound l la was determined using X-ray crystallography. A representation of the 3D structure of compound lla is shown in Figure IA. Selected crystallographic data for compound l la is shown in Table 1.

TABLE 1

Procedure J: (3.S,4/?)-4-Phenyl-Λ^f-((y)-l-phenylethyl)pyrrolidine-3-carboxamide

(Example 26)

PdIC 0C

Example 26

[0202] To a solution of (35,4/?)-l-benzyl-4-(4-chlorophenyl)-N-((S)-l- phenylethyl)pyrrolidine-3-carboxamide (Ha) (50 mg, 0.13 mmol) in methanol (3 mL) was added 10% palladium on activated charcoal (30 mg), followed by ammonium formate (200 mg, 3.17 mmol). The mixture was heated to 80 ⁰C for 30 minutes. The mixture was allowed to cool to room temperature and filtered through a pad of Celite^®. The pad was washed with 5 mL of methanol and the solvent removed in vacuo. The residue was purified by semi-preparative hplc to provide of (35',4/J)-4-phenyl-N-((.S)-l- phenylethyl)pyrrolidine-3-carboxamide (Example 26) (43 mg, 81%).

[0203] Data for (3,S,4i?)-4-phenyl-N-((5^<)-l-phenylethyl)pyrrolidine-3- carboxamide (Example 26): ¹H NMR (400 MHz, CD₃OD) δ 7.44-7.19 (m, 10H), 4.95- 4.87 (m, IH, overlap with H₂O peak), 3.80-3.66 (m, 3H), 3.49-3.40 (m, 2H), 3.24 (q, IH), 1.23 (d, 3H); MS (ESI) m/z: 385.4 [M+H]⁺.

[0204] Analogous compounds of formula Ia and/or Ib can be synthesized using similar experimental procedures. [0205] Chiral compounds of formula I may be prepared in enantiomerically pure form by separation of enantiomers via chiral high performance liquid chromatography (HPLC).

[0206] Alternatively, chiral compound of formula I can be prepared by mixing the racemic interemediate XI with a chiral base. The resulting diastereomeric salts may be separated by fractional crystallization and one or both of the diastereomers converted to the corresponding scalemic or pure enantiomers(s) by means well known to one skilled in the art. Subsequently this scalemic or enantiopure intermediate can be converted into scalemic or enantiopure compounds of formula I using the appropriate procedures summarized above.

[0207] The following is an example to demonstrate the separation of chiral salts by fractional crystallization.

Procedure K: Resolution of (+/-)-/rαm--l-(ϊerM3utoxycarbonyl>4-(4-

(trifluoromethyl)phenyl)pyrrolidine-3-carboxylic acid (5) by fractional recrystallization

(+/-)-5 12a 12b

1) recrystallize 3X from THF

2) 1 N HCI (aq)/EtOAc

<->-5 e r - 17 1

[0208] To a solution of (+/-)-fnmy-l-(/erf-butoxycarbonyl)-4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxylic acid (5) (4.7 g, 13.1 mmol) in EtOAc (100 mL) in a 250 mL Erlenmeyer flask was added (S)-(-)α-methylbenzylamine (1.68 mL, 13.1 mmol). The flask was swirled by hand to mix and then allowed to stand at room temperature for 3 h, after which a white precipitate had formed. The white solid was collected by filtration to give ~5 g of a mixture of diastereomeric salts 12a and 12b. This was recrystallized from THF (-50-100 mL) giving 3.48 g of white solid. This was recrystallized a second time from THF giving 2.40 g of white solid. Finally, a third recrystallization from THF gave 1.83 g of white solid. 20 mgs of this material was derivatized as described below (Procedure L) and the crude product analyzed by ¹H NMR to show a diastereomeric ratio (d.r.) of 17: 1.0. The remaining 1.81 g of material was partitioned between EtOAc (100 mL) and 1 M HCl (aq) (50 mL) by shaking vigorously in a separatory funnel until both layers were clear. The layers were separated and then the organic layer was washed with additional 1 M HCl (aq) (1 X 40 mL) and brine (1 X 30 mL), dried (Na₂SO₄), filtered and concentrated in vacuo to afford 1.41 grams of scalemic compound 5. Recrystallization of 54 mg of scalemic compound 5 from EtOAc/hexanes provided 30 mg of an analytical sample for analysis.

[0209] Data for scalemic compound 5: ¹H NMR (400 MHz, J6-DMSO) δ 12.57 (br s, IH), 7.69 (d, IH), 7.58 (d, IH), 3.75 (m, 2H), 3.63 (m, IH), 3.48-3.22 (m, 3H, partially obscured by H₂O peak), 2.81 (d, 3H); [α]²³ _D -34.7° (c 1.25, MeOH) Procedure L: Derivatization into diastereomeric amides and ¹H NMR analysis to obtain the diastereomeric ratio (d.r.) of amides 13a and 13b

13b

[0210] A mixture of diastereomeric salts 12a and 12b (20 mg, 0.042 mmol), obtained after fractional recrystallization from THF (see Procedure K above), was suspended in CH₂Cl₂ (1 mL) and DMF (0.1 mL) and to this were added EDC (10 mg, 0.050 mmol) and HOBt monohydrate (7 mg, 0.050 mmol). The resultant mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The crude residue was partitioned between EtOAc (4 mL) and 1 M HCl (aq) (2 mL) and then the organic phase was washed with additional 1 M HCl (aq) (2 mL), sat. NaHCO₃ (aq) (1 X 2 mL) and water (1 X 2 mL). The organic phase was then dried (Na₂SO₄), filtered and concentrated in vacuo to afford 18 mg of a mixture of crude amides 13a and 13b. A ¹H NMR spectrum of the crude diastereomeric amides in CDCl₃ was obtained and the d.r. was determined by comparison of the integrations of the aromatic peaks at 7.63 ppm (d, 2H, Ar-H of amide 13a) and at 7.49 ppm (d, 2H, Ar-H of amide 13b) and/or 6.87 ppm (t, 2Η, Ar-H of amide 13b). By this method the d.r. was determined to be 17:1.0.

[0211] Preparations of specific Examples utilizing general Procedures A to L are further illustrated as follows.

Preparation of Example 32 - (35,4^)-AMYSV l-phenylethyl)-4-(4- (trifluoromethyl)phenyl)pyiτolidine-3-carboxarnide

Example 32

(+/-)-trα«5-l-(tert-Butoxycarbonyl)-4-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxylic acid (+/-)5 (20 g, 55.7 mmol, 1.0 eq., prepared from Procedures A to D) was dissolved in 300 mL DCM (300 mL), (S)-l-phenylethylamine (7 g, 57.8 mmol, 1.04 eq.), EDC (16 g, 83.2 mmol, 1.5 eq.) and HOBt (12 g, 83.2 mmol, 1.5 eq.) were added. The mixture was stirred at 25 ⁰C for 8 h. The mixture was diluted with H₂O (200 mL) and extracted with EtOAc. The organic layers were dried, concentrated, and the residue was purified by flash chromatography (Petroleum ether: EtOAc =20: 1 (VfV)) to provide the preferred (less polar) diastereomer, 13a (1O g, yield: 40 %).

[0212] 13a (10 g, 21.6 mmol) was dissolved in HCI/MeOH solution (50 mL), and stirred at 25 ⁰C for 2 h. Then the solvent were removed in vacuo to give the HCl salt of (35,4i?)-N-((5)-l-phenylethyl)-4-(4-(tπfluoromethyl)phenyl)pyrrolidine-3- carboxamide Example 32 as a white solid (8.0 g, 93 %). ¹H NMR Data for Example 32 (see Table 5). Preparation of Example 56 - (3.9,4^)-iV-((5)-l-(3-methoxyphenvnethylV4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide

Example 56

(+/-)-trα«5-l-(/er/-butoxycarbonyl)-4-(4-(trifluoromethyl)phenyl)pyrrolidine-3- carboxylic acid (+/-)5 (15 g, 42 mmol, prepared from Precedures A to D) was dissolved in 200 mL dry THF, (S)-m-methoxy-l-phenylethylamine (7.6 g, 50 mmol; Alfa Aesar, MA, USA), EDC (12.1 g, 63 mmol), HOBt (24 g, 63 mmol) and Et₃N (10 mL) were added. The mixture was stirred at rt overnight. The mixture were diluted with 200 mL H₂O, and extracted with EtOAc. The organic layer was washed with saturated NaHCO₃, then dried over Na₂SO₄ and concentrated. The residue was purified by flash chromatography (Petroleum ether: EtOAc = 10: 1 (V/V)) to give 14a as a colorless oil (5 g, yield: 30%). 14a (5.0 g, 12.8 mmol) was dissolved in HCl/MeOH solution (200 mL), and stirred at rt for 2 hrs. Then the solvent were removed in vacuo to give the HCl salt of (3S,4R)-N-((S)- l-(3-methoxyphenyl)ethyl)-4-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxamide Example 56 as a white solid (4.7 g, 100%). ¹H NMR Data for Example 56 (see Table 5). Preparation of Example 96 - (3S.4R)-N-((S)-l-m-tolylethylV4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide

(S)-l-m-tolylethanamine was resolved by fractional recrystallization according to the following procedures.

[0213] Succinic anhydride 15 (50 g, 50.0 mmol) was dissolved in 750 mL of diethyl ether at rt, and a solution of (R)-α-phenylethylamine (60 g, 50.0 mmol) in 15 mL diethyl ether was added dropwise over 10 min with stirring. The resulting mixture was stirred for 5 hrs at rt. Precipitate was filtrated to give the product 17 as a white solid (39 g, 79.0%). Racemic 4-methyl-phenylethylamine 18 (20 g, 148 mmol) and N-(I-(R)- phenylethyl)-succinamic acid 17 (33 g, 148 mmol) were dissolved in acetone (120 mL). The mixture allowed to stand at rt for 12 hrs, a white solid 19 (35.7 g) was collected by filtration. To a reaction flask was added the mixture 19 (35.7 g), then it was recrystallized from 170 mL acetone to give the first recrystallization product (18 g). The material was recrystallized two additional time 100 mL and 60 mL acetone to yield the chiral salt 20 (5 g) as a white solid. The chiral salt 20 (5 g, 14 mmol) was dissolved in water (12 mL), 20% aqueous HCl (5 mL) added and the mixture washed by EtOAc (3x 10 mL). To the aqueous phase, NaOH (3 g) was added and extracted by EtOAc (4^χ lO mL). The combined organic phase was dried over Na₂SO₄ and the solvent evaporated to give the (S)-l-m-tolylethanamine 21 as colorless oil (1.6 g, 8%).

(-)-5

22 Example 96

(-)-5 (3.5 g, 10 mmol, prepared from Procedure K) was dissolved in 90 mL DCM, and (S)-l-m-tolylethanamine 21 (1.3 g, 10 mmol), EDC (4 g, 10 mmol), HOBt (650 mg, 1 mmol). The mixture was stirred at rt for 5 h. The mixture was diluted with H₂O (10OmL), and extracted with EtOAc. The organic layers were dried and concentrated. The crude material was purified by semi-preparative HPLC to give compound 22 (4.0 g, 87 %). [0214] Compound 22 (4.5 g, 9.4 mmol) was dissolved in HCl-MeOH solution (-1.25 M, 100 niL), and was stirred at rt for 3 hrs. The solvent were removed in vacuo to give HCl salt of (3S,4R)-N-((S)-l-m-tolylethyl>4-(4-(trifluoromethyl)phenyl)pyrrolidine- 3-carboxamide Example 96 (3.3 g, 94%) as a white solid. ¹H NMR Data for Example 96 (see Table 5).

[02151 Preparation of Example 72 - (3£4fl)-iV-((y)-l-(6-methoxypyridin-2- yl)ethyl)-4-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxamide

(S)-I -(6-methoxypyridin-2-yl)ethanamine (51) was prepared by the following procedures.

45 47 48

49 50 51

[0216] In a 250 mL of round bottom flask, equipped with Dean-Stark trap and a reflux condenser, 6-methoxypicolinaldehyde 45 (500 mg, 3.65 mmol), (S)-2 (+)- phenylglycinol 46 (500 mg, 3.65 mmol) and anhydrous THF (30 mL) were mixed and heated at reflux under argon for 4 h. (S,E)-2-((6-methoxypyridin-2-yl)methyleneamino)- 2-phenylethanol 47 was used directly in the next step without further purification.

[0217] HDMS (470 mg, 2.92 mmol), (NH₄)₂SO₄ (53 mg, 0.4 mmol) and anhydrous THF (15 mL) were added to compound 47 (934 mg, 3.65 mmol). The reaction mixture was heated at 80⁰C for 2 h under argon. Then the solvent was removed in vacuo to afford crude (S,E)-N-((6-methoxypyridin-2-yl)methylene)-l-phenyl-2-

(trimethylsilyloxy)ethanamine 48 (1.2 g).

[0218] In a 100 mL of round bottom flask (flame-dried), at -78 "C, were added anhydrous THF (10 mL) and CH₃MgBr (3.0 M in Et₂O, 3.5 mL). At -50 ⁰C, compound 48 (1.2 g, 3.65 mmL) in anhydrous THF (10 mL) was added dropwise. The reaction mixture was stirred at -40 ⁰C for 1 h, and at rt. for 1 h. The reaction was then quenched with a cold, sat. NH₄Cl with stirring at 0⁰C. EtOAc was added and layers were separated. The organic layer was concentrated to afford (S)-N-((S)-l-(6-methoxypyridin- 2-yl)ethyl)-l-phenyl-2-(trimethylsilyloxy)ethanamine 49 (1 g).

[0219] A solution of compound 49 (1 g, 0.29 mmol) in THF was cooled to 0 °C, H₂SO₄ (2.5 M, 5 rnL) was added dropwise with stirring. The resulting mixture was stirred at rt. for 2 h. The mixture was basified with 2N NaOH at 0 ^°C and extracted with EtOAc (3 x 30 mL). Combined organic layers were dried over Na₂SO₄ and concentrated. The residue was purified with flash column (eluted with 30% EtOAc/hexane) to give (S)- 2-((S)-l-(6-methoxypyridin-2-yl)ethylamino)-2-phenylethanol 50 (860 mg).

[0220] Methylamine in water (40 % in water, 10 mL) was added to a solution of compound 50 (860 m g, 3.16 mmol) in MeOH (15 mL). At 0 ⁰C, H₅IO₆ (4.33 g,) in water (15 mL) was added dropwise. White precipitates were formed. The resulting mixture was stirred at rt overnight. EtOAc and water were added. Organic layer was separated, and aq. layer was extracted with EtOAc. Combined organic layers were concentrated. The crude product was purified by prep. HPLC to give (S)-I -(6- methoxypyridin-2-yl)ethanamine 51 (80 mg).

[0221] Data for compound 51: ¹H NMR (400 MHz, CD₃OD) δ 7.62 (t, IH), 6.89 (d, IH), 6.64 (d, IH), 3.97 (m, IH), 3.90 (s, 3H), 1.42 (d, 3H).

[0222] The above method can be used to prepare other chiral amines. For examples, the chiral amines used in Example 117, 118 and 120.

(-)-5 52 Example 72

[0223] Example 72 was prepared from (-)-5 (prepared from Procedure K) and (S)-l-(6-methoxypyridin-2-yl)ethanamine 51 using the similar procedures in Example 96. ¹H NMR Data for Example 72 (see Table 5). Preparation of Example 91 - (3S,4R)-4-(3,4-dichlorophenyl)-N-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide

23 24 25

26 27 28

1 -benzyl-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylate 25 was prepared from 3,4-dichlorobenzaldehyde 23 (Aldrich, MO, USA) according to Procedure A and B. The debenzylation and Boc-protection steps were conducted as follows:

[0224] Compound 25 (63.3 g, 174 mmol) was dissolved in 500 mL 1,2- dichloroethane. To the solution was added ACE-Cl (50 g, 348 mmol) and n-Bi^NI (19 g, 52 mmol). The mixture was heated to reflux for 10 hrs. After cooling to 25 ⁰C, the solvent was evaporated and the residue was added 400 mL MeOH, heated to reflux for 3 hrs. Then the solvent were removed in vacuo and the residue was purified by flash chromatography (Petroleum etheπEtOAc =10: 1 (VfV) to MeOH) to give compound 26 as a yellow oil (50 g, 93%). To a solution of compound 26 (50 g, 163 mmol) in 200 mL THF was added BoC₂O (54 g, 242 mmol) and TEA (30 mL) at 0 ⁰C. The mixture was stirred at rt for 18 h. The solvent was removed in vacuo and the crude product was purified by flash chromatography (Petroleum etheπEtOAc =20: 1 (VZV)) to compound 27 as an oil (51 g, 84%). Compound 27 was hydrolysed to the acid 28 as in Procedure D and then coupled with (S)-l-(3-methoxyphenyl)ethanamine and the resulting diastereomers were separated as in procedure F to yield chiral compound 29. It was then converted to the HCl salt of (3S,4R)-4-(3,4-dichlorophenyl)-N-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide Example 91 according to Procedure G. ¹H NMR Data for Example 91 (see Table 5). Preparation of Example 106 - (3S,4R)-4-(4-ethylphenylVN-((S)-l -(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide

Similarly prepared as in

Similarly prepared as in Proceduer D Proceduer C2

35

34

[0225] HCl salt of (3S,4R)-4-(4-ethylphenyl>N-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide Example 106 was prepared from 4- ethylbenzaldehyde 30 (Aldrich, MO, USA) according to Procedure A, B, C2, D, F and G. ¹H NMR Data for Example 106 (see Table 5).

[0226] The aryl aldehyde II in Scheme 1 can be substituted with heteroarylaldehydes, this will yield compounds with a formula Ic and Id. Synthetic methods in Scheme 1 to 5 and Procedure A to L can be applied to prepare such compounds with a heteroaryl substitution as shown in formula Ic and Id.

HetAr = Heteroaryls Preparation of Example 113 - (3S,4S)-4-(5-chlorothiophen-2-ylVN-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide

Cl

37 38 39

Similarly prepared as in (i) ACE-CI , DCM, it BoC₂O Procedure B (H) MeOH, reflux

40 41

as in

[0227] A solution of 2-chlorothiophene 37 (48 g, 0.4 mol; Aldrich, MO, USA) in dry THF (500 mL) was cooled to -78 ⁰C, 2.5 M n-BuLi (240 mL, 0.6 mol) was added slowly, and the resulting mixture was stirred for 1 h at -78 ⁰C. DMF (48 g, 0.6 mol) was added dropwise at -78 ⁰C. After the addition, the reaction was allowed to warm up to rt gradually and stirred for at rt for 6 h. The solvent was evaporated to give crude 5- chlorothiophene-2-carbaldehyde 38 as a yellow oil (58 g, 97 %). MS (ESI) m/z: 146.7 + 148.7 [M+H]⁺. 38 was converted to compound 40 according to procedure A and B. The debenzylation and Boc-protection steps were conducted as follows:

[0228] To a solution of 40 (80 g, 0.24 mol) in dry DCM (500 mL) was added ACE-Cl (193 g, 1.00 mol), the mixture was stirred at rt 6 h. The solvent was removed in vacuo, the residue was dissolved in MeOH (500 mL) and stirred under reflux for 1 h. Then the crude was purified on silica gel to give compound 41 as a yellow oil (6 g, 10 %). To a solution of 41 (6 g, 24 mmol) in H₂O (20 mL) and MeOH (60 mL) was added Boc₂O (10 g, 48 mmol) and Na₂CO₃ (10.6 g, 100 mmol). The mixture was stirred at rt overnight. Then the solvent was removed and the crude product was purified by flash chromatography to give compound 42 as a yellow oil (7 g, 83 %).

[0229] Compound 42 was converted to the HCl salt of (3S,4S)-4-(5- chlorothiophen-2-yl)-N-((S)-l-(3-methoxyphenyl)ethyl)pyrrolidine-3-carboxamide Example 113 according to Procedure D, F and G. ¹H NMR Data for Example 113 (see Table 5).

[0230] Table 2 shows representative methods to prepare furanylpyrrolidine analogs, and summarizes the general procedures used to prepare three representative examples of furanylpyrrolidine analogs (Example 111, Example 114 and Example 115). The compounds were prepared from commercially available aldehydes using the same or similar procedures reported for previous examples.

[0231] Table 3 shows representative methods to prepare pyridylpyrrolidine analogs , and summarizes the procedures used to prepare two representative examples of pyridylpyrrolidine analogs (Example 110 and Example 112). The compounds were prepared from commercially available aldehydes using the same or similar procedures reported for previous examples. TAB LE 3

Analytical LC/MS analysis

[0231] Method A: Waters Millenium Micromass ZQ/2996PDA separations system employing a Phenomenex Luna, 3μ C 18, 50 x 2.00 mm analytical column. The aqueous acetonitrile based solvent gradient involves:

[0232] 0 - 0.25 min - Isocratic 10% of (0.05% TFA/ acetonitrile); 0.25 min - 2.75 min - Linear gradient of 10 - 90% of (0.05% TFA/acetonitrile): 2.75 min - 3.75 min - Isocratic 90% of (0.05% TFA/acetonitrile); 3.75 min - 4.00 min - Linear gradient of 90 - 10% of (0.05% TFA/acetonitrile); 4.00 min - 5.00 min - Isocratic 10% of (0.05% TFA/acetonitrile). Flow rate = 0.5 mL/min.

[0233] Method B: Agilent 1200 LC / 61 10 MSD analytical system employing an Agilent Zorbax SB-Aq, 3.5um, 2.1 x 50 mm analytical column. The aqueous acetonitrile based solvent gradient involves:

[0234] 0 - 0.4 min - Isocratic 10% of (0.05% TFA/acetonitrile); 0.4 min - 3.4 min - Linear gradient of 10 -100 % of (0.05% TFA/acetonitrile); 3.4min - 3.9 min - Isocratic 100% of (0.05% TFA/acetonitrile); 3.9 min - 3.95 min - Linear gradient of 100 - 10% of (0.05% TFA/ acetonitrile), 3.95min - 4.5 min - Isocratic 10% of (0.05% TFA/ acetonitrile). Flow rate = 0.8 ml/min. [0235] Method C: Waters Millenium 2690/996PDA separations system employing a Phenomenex Columbus 5μ Cl 8 column 50 x 4.60 mm analytical column. The aqueous acetonitrile based solvent gradient involves:

[0236] 0 - 0.5 min - Isocratic 10% of (0.05% TFA/ acetonitrile); 0.5 min - 5.5 min - Linear gradient of 10 - 90% of (0.05% TFA/acetonitrile): 5.5 min - 7.5 min - Isocratic 90% of (0.05% TFA/acetonitrile); 7.5 min - 8 min - Linear gradient of 90 - 10% of (0.05% TFA/acetonitrile); 8 min - 10 min - Isocratic 10% of (0.05% TFA/acetonitrile). Flow rate = 0.4 mL/min;

[0237] Method D: Waters Millenium 2690/996PDA separations system employing a Phenomonex Luna 3μ C8 50 x 4.6 mm analytical column. The aqueous acetonitrile based solvent gradient involves:

[0238] 0 - 1 min - Isocratic 10% of (0.1% TFA/acetonitrile); 1 min - 7 min - Linear gradient of 10 - 90% of (0.1% TFA/acetonitrile); 7 min - 9 min - Isocratic 90% of (0.1% TFA/acetonitrile); 9 min - 10 min - Linear gradient of 90 - 10% of (0.1 % TFA/acetonitrile); 10 min - 12 min - Isocratic 10% of (0.1% TFA/acetonitrile). Flow rate = 1 mL/min;

[0239] Method E: Waters Millenium 2690/996PDA separations system employing a Phenomonex Luna 3μ C8 50 x 4.6 mm analytical column. The aqueous acetonitrile based solvent gradient involves:

[0240] 0 - 1 min - Isocratic 10% of (0.1 % TFA/acetonitrile); 1 min - 24 min - Linear gradient of 10 - 65% of (0.1% TFA/acetonitrile); 24 min - 25 min Linear gradient of 65 - 90% of (0.1% TFA/acetonitrile); 25 min - 27 min - Isocratic 90% of (0.1 % TFA/acetonitrile); 27 min - 28 min - Linear gradient of 90 - 10% of (0.1% TFA/acetonitrile); 28 min - 30 min - Isocratic 10% of (0.1% TFA/acetonitrile). Flow rate = 1 mL/min. NMR Spectroscopy

^{|024i) i}pj -^jyi^ spectroscopy was conducted using a Varian 300 MHz Gemini

2000 FTNMR or a Bruker 400 MHz Avance II FTNMR. Chemical structure naming

[0242] Compound names were generated using "Convert Structure to Name" function in ChemDraw version 8.8.0 (ChembridgeSoft Corporation, MA, USA). Sst4 GTPγS agonist assay

[0243] The agonist activity of sst₄ ligands was assessed using a cell membrane-based GTPγS assay described herein or similar assay known in the art. This functional assay utilizes a Scintillation Proximity Assay (SPA) in a 384-well format with cell membranes containing human sst₄ and test compounds to monitor the GDP to GTP exchange that occurs when this G-protein coupled receptor is activated by an agonist ligand. Briefly, CHO-Kl cells stably expressing human sst₄ are dounce homogenized in HEPES buffer with protease inhibitor (50 mM HEPES pH 7.4, 1 mM EDTA and IX protease inhibitor cocktail), and the sst₄ containing membranes are purified from the cell lysate by ultracentrifugation in a Beckman 70.1 rotor, 45,000 rpm at 4 ⁰C for 30 min. Pellets are resuspended in HEPES buffer as described above, and protein determination is performed, after which cell membranes are rapidly frozen in dry-ice and stored at -80 ⁰C until SPA assay.

[0244] For the SPA portion of the assay, serial dilutions of test compounds and the somatostatin control (Sigma Cat. No. S 1763) are made in 100% DMSO to IOOX final concentration. Compounds are then diluted 25X in assay buffer (20 nM HEPES pH 7.4, 300 mM NaCl, 10 mM MgCl₂, 0.2% BSA) in the 384-well assay plate (Corning Cat. No. 3653). 2 μg/ well of SSt₄ membrane, 50 ug/well of WGA SPA beads (GE Healthcare Cat. No. RPNQOOOl) and 10 μM guanosine diphosphate (sodium salt, Sigma Cat. # G7127) are gently mixed and then 20 μl/well of the mixture is dispensed into the assay plate containing compound. [³⁵S]-GTPyS (Perkin Elmer NEG030H, 10 μM stock) is thawed, diluted 1OX in assay buffer, and 10 μL is dispensed per well. Final well volume is 40 μL. Assay plate is centrifuged at 1000 rpm for 2 min, incubated overnight at room temperature, and then counted at 1 min per well on a Wallac Trilux Microbeta counter. C₅₀ and E_max results are calculated using GraphPad Prism, using the somatostatin dose- response curve as the 100% efficacy comparator. EC₅₀ values for representative examples are shown in Table 4.

TABLE 4

[0245] Unless otherwise specified by an asterisk, compounds in Table 5 exhibited EC₅₀'s below 10 μM in the sst₄ GTPγS assay. The assignment of absolute stereochemistry (denoted by the use of dashed and solid wedges) at C(3) and C(4) of the pyrrolidine ring is made on the basis of the stereochemical precedent established in the synthesis of Example 26 (Procedures H-J) described herein. The X-ray crystal data for intermediate 11a (Procedure I) illustrates the relative trans-relationship between the C(3) and C(4) positions on the pyrrolidine ring and (by virtue of the known absolute configuration of the iV-benzyl moiety) the absolute configuration at C(3) and C(4). Table 5 summarizes the structure and activity for example compounds.

TABLE 5

[0246] Additional compounds that can be made using the methods described herein are listed in Table 6.

TABLE 6

Example Structure

[0247] All references cited herein are incorporated herein by reference in their entirety. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.

[0248] Unless otherwise defined, all terms (including technical and scientific terms) are to be given their ordinary and customary meaning to a person of ordinary skill in the art, and are not to be limited to a special or customized meaning unless expressly so defined herein.

[0249] Terms and phrases used in this application, and variations thereof, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term 'including' should be read to mean 'including, without limitation' or the like; the term 'comprising' as used herein is synonymous with 'including,' 'containing,' or 'characterized by,' and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term 'example' is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; adjectives such as 'known', 'normal', 'standard', and terms of similar meaning should not be construed as limiting the item described to a given time period or to an item available as of a given time, but instead should be read to encompass known, normal, or standard technologies that may be available or known now or at any time in the future; and use of terms like 'preferably,' 'preferred,' 'desired,' or 'desirable,' and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. Likewise, a group of items linked with the conjunction 'and' should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as 'and/or' unless expressly stated otherwise. Similarly, a group of items linked with the conjunction 'or' should not be read as requiring mutual exclusivity among that group, but rather should be read as 'and/or' unless expressly stated otherwise. In addition, as used in this application, the articles 'a' and 'an' should be construed as referring to one or more than one (i.e., to at least one) of the grammatical objects of the article. By way of example, 'an element' means one element or more than one element.

[0250] The presence in some instances of broadening words and phrases such as 'one or more', 'at least', 'but not limited to', or other like phrases shall not be read to mean that the narrower case is intended or required in instances where such broadening phrases may be absent.

[0251] All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term 'about.' Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

[0252] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it is apparent to those skilled in the art that certain changes and modifications may be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention to the specific embodiments and examples described herein, but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention.

Claims

WHAT IS CLAIMED IS:

1. A mixture of stereoisomers or salts thereof falling within the genus described by formula I:

wherein

R¹ and R² are each independently selected from hydrogen and (C]-C₆) alkyl or together, R¹ and R² form a (C₃-C₆) cycloalkyl;

R³ is selected from hydrogen and (Ci-C₆) alkyl;

R⁴ is selected from optionally substituted heterocyclyl and optionally substituted aryl, with the proviso that R⁴ is not/?αra-cyanophenyl;

R⁵ is chosen from optionally substituted heterocyclyl and optionally substituted aryl, with the provisos that R⁵ is not /?αrα-methoxyphenyl or para- chlorophenyl, and that when R⁵ is pyridinyl or pyrimidinyl, R¹ must be (Cj-C₆) alkyl; and at least 51% of said mixture contains the 3 S configuration of the pyrrolidine.

2. A mixture of stereoisomers or salts thereof falling within the genus described by formula:

wherein

R¹ and R² are each independently selected from hydrogen and (Ci-C₆) alkyl or together, R¹ and R² form a (C₃-C₆) cycloalkyl;

R³ is selected from hydrogen and (Ci-C₆) alkyl;

R⁴ is selected from optionally substituted heterocyclyl and optionally substituted aryl, with the proviso that R⁴ is not/?αrα-cyanophenyl; and

R⁵ is chosen from optionally substituted heterocyclyl and optionally substituted aryl, with the provisos that R⁵ is not /?αrø-methoxyphenyl or para- chlorophenyl, and that when R⁵ is pyridinyl or pyrimidinyl, R¹ must be (Ci-C₆) alkyl.

3. The mixture or salts thereof of claims 1 or 2, wherein R³ is hydrogen.

4. The mixture or salts thereof of claim 3, wherein R⁴ and R⁵ are each optionally substituted aryl.

5. The mixture or salts thereof of claim 4 of formula:

wherein R is selected from hydrogen, trifluoromethyl, chloro, fluoro, (Ci- C₆) alkyl, (Cj-C₆) alkyoxy and trifluoromethoxy; R⁹ and R¹⁰ are each independently chosen from hydrogen, halogen, (Ci-Ce) alkyl, trifluoromethyl, (Ci-C₆) alkoxy, trifluoromethoxy and cyano; or

R⁸ and R⁹ together, or R⁹ and R¹⁰ together, along with the phenyl to which they are attached, can form napthyl;

R¹¹ and R¹² are each independently hydrogen, fluoro, chloro, methoxy or (Ci-C₆) alkyl; and

R¹³ is hydrogen, fluoro or methyl; or

R^{1 1} and R¹² together, or R¹² and R¹³ together, along with the phenyl to which they are attached, can form napthyl.

6. The mixture or salts thereof of claim 5, wherein R¹ is methyl or ethyl, and R² is hydrogen.

7. The mixture or salts thereof of claim 6, wherein the R¹ -bearing carbon is in the S configuration.

8. The mixture or salts thereof of claim 5, wherein R¹ and R² are both methyl, are both hydrogen, or together R¹ and R² form a (C₃-C₆) cycloalkyl.

9. The mixture or salts thereof of claim 1 or 2, wherein R³ is optionally substituted pyridin-2-yl, pyridin-3-yl or indole.

10. The mixture or salts thereof of claim 2 selected from the group consisting of:

(+,-)-trans-4-(4-ch\oropheny\)-N-( 1 -(4- fluoropheny^cyclopropy^pyirolidine^-carboxamide, trαrø-4-(4-chlorophenyl)-N-((5)-l-(4-fluorophenyl)ethyl)pyrrolidine-3- carboxamide,

(+,-)-tram'-N-benzyl-4-(4-(triiluoromethyl)phenyl)pyrrolidine-3- carboxamide,

(+,-)-trα«5-N-benzyl-4-(4-fluorophenyl)pyrrolidine-3-carboxamide,

(+,-)-/rαrø-N-benzyl-4-(2-chlorophenyl)pyrrolidine-3-carboxamide, rrara-N-((5)-l-phenylethyl)-4-(4-(trifluoromethyl)phenyl)pyrrolidine-3- carboxamide,

(+,-)-trarø-4-(4-chlorophenyl)-iV-( 1 -(4- fluorophenyl)cyclopropyl)pyrrolidine-3-carboxamide,

(+,-)-rrαrø-4-(4-methoxyphenyl)-N-(2-phenylpropan-2-yl)pyrrolidine-3- carboxamide, (+,-)-trøft.ϊ-iV-(2-phenylpiOpan-2-yl)-4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide,

(+,-)-/ra«5-jV-benzyl-4-(4-chlorophenyl)pyrrolidine-3-carboxamide, and (+,-)-rrα«5-Λ^-(3-methoxybenzyl)-4-(4-chlorophenyl)pyrrolidine-3- carboxamide.

1 1. A compound or salt thereof of formula:

wherein the configuration of the pyrrolidine ring is 3S;

R¹ and R² are each independently selected from hydrogen and (Ci-C₆) alkyl, or together R¹ and R² form a (C₃-C₆) cycloalkyl;

R³ is selected from hydrogen and (Ci-C₆) alkyl;

R⁴ is selected from optionally substituted heterocyclyl and optionally substituted aryl, with the proviso that R⁴ is not/?αrα-cyanophenyl;

R⁵ is chosen from optionally substituted heterocyclyl and optionally substituted aryl; and

Y is a direct bond or -CH₂ or together, Y and R¹ can form a cyclopropane; with the provisos that when R⁵ is pyridinyl or pyrimidinyl, R¹ must be (Q- C₆) alkyl and that when Y is a direct bond, R⁵ is not/?αrα-methoxyphenyl or para- chlorophenyl.

12. The compound or salt thereof of claim 1 1 , wherein R³ is hydrogen.

13. The compound or salt thereof of claim 1 1 or 12, wherein Y is a direct bond, R¹ is methyl or ethyl and R² is hydrogen.

14. The compound or salt thereof of claim 11 or 12, wherein Y is CH₂.

15. The compound or salt thereof of any one of claims 1 1 to 14, wherein the R^!-bearing carbon is in the S configuration.

16. The compound or salt thereof of any one of claims 1 1 to 15, wherein R and R⁵ are each optionally substituted aryl.

17. The compound or salt thereof of claim 16, wherein R⁴ and R⁵ are each optionally substituted phenyl or naphthyl.

18. The compound or salt thereof of any one of claims 1 1 to 17, wherein R⁴ and R⁵ are independently aryl or heteroaryl each optionally substituted by 1 or 2 substituents independently selected from the group consisting of Ci-C₄ alkyl (e.g. methyl), Ci-C₄ alkoxy (e.g. methoxy), halogen (e.g. chlorine, fluorine), trifluoromethyl and trifluoromethoxy.

19. The compound or salt thereof of claim 18, wherein R⁵ is optionally substituted thiophenyl or optionally substituted furanyl.

20. The compound or salt thereof of claim 1 1 , wherein R³ is optionally substituted pyridin-2-yl, pyridin-3-yl or indole.

21. The compound or salt thereof of claim 1 1 , wherein R⁴ is optionally substituted heterocycle.

22. The compound or salt thereof of claim 21, wherein R⁴ is optionally substituted thiophene or optionally substituted furan or optionally substituted pyridine.

23. The compound or salt thereof of claim 16 of formula:

wherein R is hydrogen, trifluoromethyl, chloro, fluoro, (Ci-C₆) alkyl, (Ci- C₆) alkyloxy or trifluoromethoxy;

R⁹ and R¹⁰ are each independently chosen from hydrogen, halogen, (C]-C₆) alkyl, trifluoromethyl, (Ci-C₆) alkoxy, trifluoromethoxy and cyano; or

R⁸ and R⁹ together, or R⁹ and R¹⁰ together, along with the phenyl to which they are attached, can form napthyl; R^{1 1} and R¹² are each independently hydrogen, fluoro, chloro, methoxy or (C₁-C₆) alkyl; and

R¹³ is hydrogen, fluoro or methyl; or

R^{1 1} and R¹² together, or R¹² and R¹³ together, along with the phenyl to which they are attached, can form napthyl.

24. The compound or salt thereof of claim 23, wherein Y is a direct bond, R is methyl or ethyl and R² is hydrogen.

25. The compound or salt thereof of claim 23, wherein the R '-bearing carbon is in the S configuration.

26. The compound or salt thereof of claim 23, wherein R¹ and R² are both methyl, are both hydrogen or together R¹ and R² form a (C₃-C₆) cycloalkyl.

27. The compound or salt thereof of claim 11 selected from the group consisting of:

(3S,4R)-4-(4-chlorophenyl)-N-((S)-l-phenylethyl)pyrrolidine-3- carboxamide,

(3S,4R)-4-(4-chlorophenyl)-N-((R)-l-phenylethyl)pyrrolidine-3- carboxamide,

(3S,4R)-4-(4-chlorophenyl)-N-((S)-l-(2-fluorophenyl)ethyl)pyrrolidine-3- carboxamide,

(3S,4R)-4-(4-chlorophenyl)-N-((S)-l-(3-methoxyphenyl)ethyl)pyrrolidine- 3-carboxamide,

(3S,4R)-4-(4-chlorophenyl)-N-((S)-l-(4-fluorophenyl)ethyl)pyrrolidine-3- carboxamide,

(3S,4R)-4-(4-chlorophenyl)-N-((S)-l-(pyridin-3-yl)ethyl)pyrrolidine-3- carboxamide,

(3S,4R)-4-(4-chlorophenyl)-N-((S)-l-(pyridin-2-yl)ethyl)pyrrolidine-3- carboxamide,

(3S,4R)-4-(4-chlorophenyl)-N-((S)-l-(3-fluorophenyl)ethyl)pyrrolidine-3- carboxamide,

(3S,4R)-4-(4-chlorophenyl)-N-((S)-l-(3-fluorophenyl)ethyl)pyrrolidine-3- carboxamide,

(3S,4R)-4-(4-chlorophenyl)-N-((R)-l-(3-fluorophenyl)ethyl)pyrrolidine-3- carboxamide, (3 S,4R)-4-(4-methoxyphenyl>N-((S)- 1 -phenylethy l)pyrrolidine-3 - carboxamide,

(3S,4R)-4-(2-methoxyphenyl>N-((S)-l-phenylethyl)pyiτolidine-3- carboxamide,

(3S,4R)-4-(3-chlorophenyl)-N-((S)-l-phenylethyl)pyrrolidine-3- carboxamide,

(3 S,4R)-N-((S)- 1 -pheny lethyl)-4-p-to Iy lpyrrolidine-3 -carboxamide,

(3S,4R)-N-((S)-l-phenylethyl>4-(3-(trifluoromethyl)phenyl)pyrrolidine-3- carboxamide,

(3S,4R)-N-((S)-l-phenylethyl)-4-(pyridin-3-yl)pyrrolidine-3-carboxamide,

(3S,4R)-4-(naphthalen-2-yl)-N-((S)-l-phenylethyl)pyrrolidine-3- carboxamide,

(3 S,4R)-4-(naphthalen- 1 -yl)-N-((S)- 1 -pheny lethyl)pyrrolidine-3- carboxamide,

(3S,4R)-4-phenyl-N-((S)-l-phenylethyl)pyrrolidine-3-carboxamide,

(3S,4S)-N-((S)-l-phenylethyl>4-(thiophen-2-yl)pyrrolidine-3- carboxamide,

(3S,4R)-4-(2-chlorophenyl)-N-((S)-l-phenylethyl)pyrrolidine-3- carboxamide,

(3 S ,4R)-4-(3 -cyanopheny 1>N-((S)- 1 -pheny lethy l)pyrrolidine-3 - carboxamide,

(3S,4R)-4-(4-methoxyphenyl)-N-((S)- 1 -phenylpropyl)pyrrolidine-3- carboxamide,

(3S,4R)-N-((S)-l-phenylethyl)-4-(4-(trifluoromethyl)phenyl)pyrrolidine-3- carboxamide,

(3 S,4R)-N-((S)- 1 -(4-fluorophenyl)ethyl>4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide,

(3S,4R)-N-((S)-l-phenylpropyl>4-(4-(trifluoromethyl)phenyl)pyrrolidine- 3 -carboxamide,

(3S,4R)-4-(4-(trifluoromethyl)phenyl)-N-((lS,2R)-2- phenylcyclopropyl)pyrrolidine-3-carboxamide,

(3S,4R)-4-(4-(trifluoromethyl)phenyl)-N-((lR,2S)-2- phenylcyclopropy^pyrrolidine-S-carboxamide, (3S,4R)-N-((R)-l-phenylpropan-2-yl)-4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide,

(3S,4R)-N-((S)-l-phenylpropan-2-yl)-4-(4- (trifluoromethyl)phenyl)pyπOlidine-3-carboxamide,

(3S,4R)-N-((R)-l-(4-chlorophenyl)propan-2-yl)-4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide,

(3S,4R)-N-((S)-l-(4-chlorophenyl)propan-2-yl)-4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide,

(3S,4R)-N-(l-phenylcyclopropyl>4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide,

(3S,4R)-N-benzyl-4-(4-(trifluoromethyl)phenyl)pyrrolidine-3- carboxamide,

(3S,4R)-N-(2-phenylpropan-2-yl)-4-(4- (trifluoromethyl)phenyl)pyrrolidineH3-carboxamide,

(3S,4R)-N-(l-(4-fluorophenyl)cyclopropyl>4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide,

(3S,4R)-N-((S)-l-phenylethyl)-4-(4-(trifluoromethoxy)phenyl)pyrrolidine- 3-carboxamide,

(3S,4R)-N-((S)-l-(3-methoxyphenyl)ethyl>4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide,

(3 S,4R)-4-(3 ,4-dichlorophenyl)-N-((S)- 1 -pheny lethy l)pyrτolidine-3 - carboxamide,

(3S,4R)-N-((S)-l-phenylpropyl>4-(4- (trifluoromethoxy)phenyl)pyrrolidine-3-carboxamide,

(3 S,4R)-N-((S)- 1 -(4-fluorophenyl)ethyl>4-(4- (trifluoromethoxy)phenyl)pyrrolidine-3-carboxamide,

(3S,4R)-4-(3,4-dichlorophenyl)-N-((S)-l-phenylpropyl)pyrrolidine_^3- carboxamide,

(3S,4R)-N-((S)-l-(3-methoxyphenyl)ethyl>4-(4- (trifluoromethoxy)phenyl)pyrrolidine-3-carboxamide,

(3S,4R)-N-((S)-l-p-tolylethyl>4-(4-(trifluoromethyl)phenyl)pyrrolidin^3- carboxamide, (3S,4R)-4-(4-(trifluoromethyl)phenyl)-N-((S)-l-(6- (trifluoromethyl)pyridin-3-yl)propyl)pyrrolidine-3-carboxamide,

(3 S,4R)-4-(2,4-dichlorophenyl)-N-((S)- 1 -pheny lpropy l)pyrrolidine-3 - carboxamide,

(3S,4R)-4-(2,4-dichlorophenyl)-N-((S)-l-phenylethyl)pyrrolidine-3- carboxamide,

(3S,4R)-N-((S)-l-(6-methoxypyridin-2-yl)ethyl)-4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide,

(3S,4R)-4-(4-chlorophenyl)-N-(naphthalen-l-ylmethyl)pyrrolidine-3- carboxamide,

(3 S,4R)-4-(4-chlorophenyl)-N-( 1 -(4-fluorophenyl)cyclopropyl)pyrrolidine- 3 -carboxamide,

(3S,4R)-N-((S)-l-(3-chlorophenyl)ethyl>4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide,

(3S,4R)-N-benzyl-4-(4-fluorophenyl)pyrrolidine-3-carboxamide,

(3S,4R)-N-(2-(lH-indol-3-yl)ethyl>4-(4-chlorophenyl)pyrrolidine-3- carboxamide,

(3S,4R)-N-((S)-l-(3-methoxyphenyl)ethyl>l-methyl-4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide,

(3S,4R)-N-benzyl-4-(2-chlorophenyl)pyrrolidine-3-carboxamide,

(3S,4R)-4-(4-methoxyphenyl)-N-phenethylpyπOlidine-3-carboxamide,

(3S,4R)-4-(4-methoxyphenyl)-N-(2-phenylpropan-2-yl)pyrrolidine-3- carboxamide,

(3 S, 4R)-N-benzyl-4-(4-chlorophenyl)pyrrolidine-3 -carboxamide,

(3S,4R)-N-phenethyl-4-(4-(trifluoromethyl)phenyl)pyrrolidine-3- carboxamide,

(3S,4R)-N-(3-methoxybenzyl)-4-(4-chlorophenyl)pyrrolidine-3- carboxamide,

(3S,4R)-N-((R)-l-(3-chlorophenyl)ethyl)-4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide,

(3S,4R)-4-(3,5-dichlorophenyl)-N-((S)-l-phenylethyl)pyrrolidine-3- carboxamide, (3S,4R)-4-(3,5-dichlorophenyl)-N-((S)-l-phenylpropyl)pyrrolidine-3- carboxamide,

(3S,4R)-4-(3,4-dichlorophenyl)-N-((S)-l-(4- fluorophenyl)ethyl)pyrrolidine-3-carboxamide,

(3S,4R)-4-(3,4-dichlorophenyl)-N-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide'

(3S,4R)-4-(3,5-dichlorophenyl)-N-((S)-l-(4- fluorophenyl)ethyl)pyiτolidine-3-carboxamide,

(3S,4R)-4-(3,5-dichlorophenyl)-N-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide,

(3S,4R)-4-(3,5-dichlorophenyl)-N-((S)-l-(3- fluorophenyl)ethyl)pyrrolidine-3-carboxamide,

(3S,4R)-N-((S)-l-m-tolylethyl>4-(4-(trifluoromethyl)phenyl)pyrrolidin^3- carboxamide,

(3S,4R)-N-((R)-l-m-tolylethyl>4-(4-(trifluoromethyl)phenyl)pyrrolidine- 3-carboxamide,

(3S,4R)-N-((S)-l-(3-fluorophenyl)ethyl>4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide,

(3S,4R)-N-((R)-l-(3-flυorophenyl)ethyl>4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide,

(3S,4R)-N-((S)-l-(3-fluorophenyl)ethyl>4-(4- (trifluoromethoxy)phenyl)pyrrolidine-3-carboxamide,

(3S,4R)-4-(2,4-dichlorophenyl)-N-((S)-l-(3- fluorophenyl)ethyl)pyrrolidine-3-carboxamide,

(3S,4R)-4-(3,4-dichlorophenyl)-N-((S)-l-(3- fluorophenyl)ethyl)pyrrolidine-3-carboxamide,

(3S,4R)-4-(4-ethylphenyl)-N-((S)-l-phenylethyl)pyrrolidin^3- carboxamide,

(3S,4R)-4-(4-isopropylphenyl>N-((S)-l-phenylethyl)pyrrolidin&-3- carboxamide,

(3S,4R)-4-(4-tert-butylphenyl)-N-((S)-l-phenylethyl)pyrrolidine-3- carboxamide, (SS^^^^-ethylphenyiyN-CCS^l-CS-methoxyphenyOethyOpyrrolidine-S- carboxamide,

(3S,4R)-4-(4-isopropylphenyl>N-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidino-3-carboxamide,

(3S,4R)-4-(4-tert-butylphenyl>N-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide,

(3S,4R)-N-((S)-l-phenylethyl>4-(6-(trifluoromethyl)pyridin-3- yl)pyrrolidine-3-carboxamide,

(3S,4S)-N-((S)-l-phenylethyl)-4-(5-(trifluoromethyl)furan-2- yl)pyrrolidine-3-carboxamide,

(3S,4R)-N-((S)-l-(3-methoxyphenyl)ethyl>4-(6-(trifluoromethyl)pyridin- 3-yl)pyrrolidine-3-carboxamide,

(3S,4S)-4-(5-chlorothiophen-2-yl)-N-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide,

(3S,4S)-N-((S)-l-(3-methoxyphenyl)ethyl>4-(5-(trifluoromethyl)furan-2- yl)pyrrolidine-3-carboxamide,

(3S,4S)-4-(5-chlorofuran-2-yl)-N-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide,

(3S,4S)-4-(5-chlorothiophen-2-yl)-N-((S)-l-phenylethyl)pyrrolidin^3- carboxamide,

(3S,4R)-N-((S)-l-(5-methylthiophen-2-yl)ethyl>-4-(4- (trifluoromethyl)phenyl)pyπOlidine-3-carboxamide,

(3S,4R)-N-((S)-l-(5-methylfuran-2-yl)ethyl>4-(4- (trifluoromethyl)phenyl)pyπOlidine-3-carboxamide,

(3 S,4R)- 1 -methyl-N-((S)- 1 -pheny lethy l>4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide,

(3S,4R)-N-((S)-l-(5-chlorofuran-2-yl)ethyl)-4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide,

(3S,4R)-l-isopropyl-N-((S)-l-(3-methoxyphenyl)ethyl>4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide,

(3S,4R)-l-ethyl-N-((S)-l-(3-methoxyphenyl)ethyl>4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide, (3S,4R)-N-((S)-l-(2-methoxyphenyl)ethyl>4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide,

(3S,4R)-N-((S)-l-(3,5-dimethoxyphenyl)ethyl>4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide,

(3 S,4R)-N-((S)- 1 -(2-fluorophenyl)ethyl>4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide, and

(3S,4R)-N-((S)-l-(3-fluoro-5-methylphenyl)ethyl>4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide.

28. The compound or salt thereof of claim 1 1 , selected from the group consisting of:

(3S,4R)-N-((S)-l-(2-fluorophenyl)ethyl)-4-(6-(trifluoromethyl)pyridin-3- yl)pyrrolidine-3-carboxamide,

(3S,4R)-N-((S)-l-(3-fluorophenyl)ethyl>4-(6-(trifluoromethyl)pyridin-3- yl)pyrrolidine-3-carboxamide,

(3S,4R)-N-((S)-l-(4-fluorophenyl)ethyl)-4-(6-(trifluoromethyl)pyridin-3- y l)pyrrolidine-3 -carboxamide,

(3S,4R)-N-((S)-l-(3-chlorophenyl)ethyl)-4-(6-(trifluoromethyl)pyridin-3- yl)pyrrolidine-3-carboxamide,

(3S,4R)-N-((S)-l-(pyridin-2-yl)ethyl>4-(6-(trifluoromethyl)pyridin-3- yl)pyrrolidine-3-carboxamide,

(3S,4R)-N-((S)-l-(6-methoxypyridin-2-yl)ethyl)-4-(6- (trifluoromethyl)pyridin-3-yl)pyrrolidine-3-carboxamide,

(3S,4R)-N-((S)-l-(6-methylpyridin-2-yl)ethyl>4-(6- (trifluoromethyl)pyridin-3-yl)pyrrolidine-3-carboxamide,

(3S,4S)-N-((S)-l-phenylethylH-(5-(trifluoromethyl)pyridin-2- yl)pyrrolidine-3-carboxamide,

(3S,4S)-N-((S)-l-(2-fluorophenyl)ethyl>4-(5-(trifluoromethyl)pyridin-2- yl)pyrrolidine-3-carboxamide,

(3S,4S)-N-((S)-l-(3-fluorophenyl)ethyl>4-(5-(trifluoromethyl)pyridin-2- yl)pyrrolidine-3 -carboxamide,

(3S,4S)-N-((S)-l-(4-fluorophenyl)ethyl>4-(5-(trifluoromethyl)pyridin-2- yl)pyrrolidine-3 -carboxamide, (3S,4S)-N-((S)-l-(3-methoxyphenyl)ethyl>4-(5-(trifluoromethyl)pyridin- 2-yl)pyrrolidine-3-carboxamide,

(3S,4S)-N-((S)-l-m-tolylethyl>4-(5-(trifluoromethyl)pyridin-2- yl)pyrrolidine-3-carboxamide,

(3S,4S)-N-((S)-l-(3-chlorophenyl)ethyl)-4-(5-(trifluoromethyl)pyridin-2- yl)pyrrolidine-3-carboxamide,

(3S,4S)-N-((S)-l-(pyridin-2-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-2- yl)pyrrolidine-3-carboxamide,

(3S,4S)-N-((S)-l-(6-methoxypyridin-2-yl)ethyl>4-(5- (trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxamide,

(3S,4S)-N-((S)-l-(6-methylpyridin-2-yl)ethyl>4-(5- (trifluoromethyl)pyridin-2-yl)pyrrolidine-3-carboxamide,

(3S,4R)-4-(6-chloropyridin-3-yl)-N-((S)-l-phenylethyl)pyrrolidineH3- carboxamide,

(3S,4R)-4-(6-chloropyridin-3-yl)-N-((S)-l-(2- fluorophenyl)ethyl)pyiτolidine-3-carboxamide,

(3S,4R)-4-(6-chloropyridin-3-yl)-N-((S)-l-(3- fluorophenyl)ethyl)pyrrolidine-3-carboxamide,

(3S,4R)-4-(6-chloropyridin-3-yl)-N-((S)-l-(4- fluorophenyl)ethyl)pyrrolidine-3-carboxamide,

(3S,4R)-4-(6-chloropyridin-3-yl)-N-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide,

(3S,4R)-4-(6-chloropyridin-3-yl)-N-((S)-l-m-tolylethyl)pyrrolidineH3- carboxamide,

(3S,4R)-N-((S)-l-(3-chlorophenyl)ethyl)-4-(6-chloropyridin-3- yl)pyrrolidine-3-carboxamide,

(3S,4R)-4-(6-chloropyridin-3-yl)-N-((S)-l-(pyridin-2-yl)ethyl)pyrrolidine_^ 3-carboxamide,

(3 S,4R)-4-(6-chloropyridin-3-y 1)-N-((S)- l-(6-methoxypyridin-2- yl)ethyl)pyiTolidine-3-carboxamide,

(3S,4R)-4-(6-chloropyridin-3-yl)-N-((S)-l-(6-methylpyridin-2- yl)ethyl)pyrrolidine-3-carboxamide, (3S,4S)-4-(5-chloropyridin-2-yl)-N-((S)-l-phenylethyl)pyrrolidine-3- carboxamide,

(3S,4S)-4-(5-chloropyridin-2-yl)-N-((S)-l-(2- fluorophenyl)ethyl)pyiτolidine-3-carboxamide,

(3 S,4S)-4-(5-chloropyridin-2-y 1)-N-((S)- 1 -(3- fluorophenyl)ethyl)pyrrolidine-3-carboxamide,

(3S,4S)-4-(5-chloropyridin-2-yl)-N-((S)-l-(4- fluorophenyl)ethyl)pyrrolidine-3-carboxamide,

(3S,4S)-4-(5-chloropyridin-2-yl)-N-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide,

(3S,4S)-4-(5-chloropyridin-2-yl)-N-((S)-l-m-tolylethyl)pyrrolidin^3- carboxamide,

(3S,4S)-N-((S)-l-(3-chlorophenyl)ethyl)-4-(5-chloropyridin-2- yl)pyrrolidine-3-carboxamide,

(3S,4S)-4-(5-chloropyridin-2-yl)-N-((S)-l-(pyridin-2-yl)ethyl)pyrrolidine- 3-carboxamide,

(3S,4S)-4-(5-chloropyridin-2-yl)-N-((S)-l-(6-methoxypyridin-2- yl)ethyl)pyrrolidine-3-carboxamide,

(3S,4S)-4-(5-chloropyridin-2-yl)-N-((S)-l-(6-methylpyridin-2- yl)ethyl)pyrrolidine-3-carboxamide,

(3S,4R)-4-(4-chlorophenyl)-N-((S)-l-(3-fluorophenyl)ethyl)pyrrolidin&-3- carboxamide,

(3S,4R)-N-((S)-l-(5-chlorofuran-2-yl)ethyl)-4-(4- chlorophenyl)pyrrolidine-3-carboxamide,

(3S,4R)-4-(4-chlorophenyl)-N-((S)-l-(6-methoxypyridin-2- yl)ethyl)pyrrolidin&-3-carboxamide, and

(3S,4R)-4-(4-chlorophenyl)-N-((S)-l-(6-methylpyridin-2- yl)ethyl)pyrrolidine-3-carboxamide.

29. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof or mixture according to any one of claims 1 to 28.

30. A method of treating a disorder which is dependent upon modulation of SSt₄, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof, or mixture according to any one of claims 1-28.

31. The method of claim 30, wherein said disorder is selected from the group consisting of pain, an inflammatory condition, Alzheimer's disease, temporal lobe epilepsy, Parkinson's disease, cortical injury, and a psychiatric disorder.

32. The method of claim 30, wherein said subject is a human.

33. A compound or pharmaceutically acceptable salt or mixture thereof according to any one of claims 1-28 for use in therapy.

34. The compound or pharmaceutically acceptable salt or mixture thereof according to any one of claims 1 -28 for use in the treatment of a disorder selected from the group consisting of pain, an inflammatory condition, Alzheimer's disease, temporal lobe epilepsy, Parkinson's disease, cortical injury, and a psychiatric disorder.

35. Use of a compound or pharmaceutically acceptable salt or mixture thereof according to any one of claims 1-28 in the manufacture of a medicament for the treatment of a disorder which is dependent upon modulation of sst₄ in a subject in need thereof.

36. The use of claim 35, wherein said disorder is chosen from the group consisting of pain, an inflammatory condition, Alzheimer's disease, temporal lobe epilepsy, Parkinson's disease, cortical injury, and a psychiatric disorder.

37. A compound or salt thereof of formula:

wherein

R¹ and R² are each independently selected from hydrogen and (C]-C₆) alkyl or together, R¹ and R² form a (C₃-C₆) cycloalkyl;

R³ is selected from hydrogen and (C]-C₆) alkyl;

R is selected from optionally substituted heterocyclyl and optionally substituted aryl, with the proviso that R⁴ is notpαra-cyanophenyl; R is chosen from optionally substituted heterocyclyl and optionally substituted aryl, with the provisos that R⁵ is not pαrα-methoxy phenyl or para- chlorophenyl, and that when R⁵ is pyridinyl or pyrimidinyl, R¹ must be (Ci-C₆) alky I.

38. The compound or salt thereof of claim 37, wherein R³ is hydrogen.

39. The compound or salt thereof of claim 38, wherein R⁴ and R⁵ are each optionally substituted aryl.

40. The compound or salt thereof of claim 37, wherein R⁵ is optionally substituted pyridin-2-yl, pyridin-3-yl or indole.

41. The compound or salt thereof of claim 39 of formula:

wherein R is selected from hydrogen, trifluoromethyl, chloro, fluoro, (Ci- C₆) alkyl, (Ci-C₆) alkyoxy and trifluoromethoxy;

R⁹ and R¹⁰ are each independently chosen from hydrogen, halogen, (C)-C₆) alkyl, trifluoromethyl, (Ci-C₆) alkoxy, trifluoromethoxy and cyano; or

R⁸ and R⁹ together, or R⁹ and R¹⁰ together, along with the phenyl to which they are attached, can form napthyl;

R^{1 1} and R¹² are each independently hydrogen, fluoro, chloro, methoxy or (Ci-C₆) alkyl; and

R¹³ is hydrogen, fluoro or methyl; or

R^{1 1} and R¹² together, or R¹² and R¹³ together, along with the phenyl to which they are attached, can form napthyl.

42. The compound or salt thereof of claim 41, wherein R¹ is methyl or ethyl, and R² is hydrogen.

43. The compound or salt thereof of claim 41, wherein the R '-bearing carbon is in the S configuration.

-I l l-

44. The compound or salt thereof of claim 41, wherein R¹ and R² are both methyl, are both hydrogen, or together R¹ and R² form a (C₃-C₆) cycloalkyl.

45. A compound or salt thereof of formula:

wherein the configuration of the pyrrolidine ring is 3S;

R¹ and R² are each independently selected from hydrogen and (Ci-C₆) alkyl, or together R¹ and R² form a (C₃-C₆) cycloalkyl;

R³ is selected from hydrogen and (Ci-C₆) alkyl;

R⁴ is selected from optionally substituted heterocyclyl and optionally substituted aryl, with the proviso that R⁴ is not/?αrα-cyanophenyl;

R⁵ is chosen from optionally substituted heterocyclyl and optionally substituted aryl; and

Y is a direct bond or -CH₂ or together, Y and R¹ can form a cyclopropane; with the provisos that when R⁵ is pyridinyl or pyrimidinyl, R¹ must be (Ci- C₆) alkyl and that when Y is a direct bond, R⁵ is not pαrα-methoxyphenyl or para- chlorophenyl.

46. A compound which is (35,4i?)-4-(4-chlorophenyl)-N-((5)-l- phenylethyl)pyrrolidine-3-carboxamide, or salt thereof.

47. A compound which is (35¹,4/?)-4-(4-chlorophenyl)-τV-((5)-l-(pyridin-3- yl)ethyl)pyrrolidine-3-carboxamide, or salt thereof.

48. A compound which is (35^>,4/?)-N-((5)-l-phenylethyl>4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide, or salt thereof.

49. A compound which is (3S,4#)-N-((S)-l-(3-methoxyphenyl)ethyl>4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide or salt thereof.

50. A compound which is (3S,4R)-N-((S)- 1 -(6-methoxypyridin-2-yl)ethy 1>4- (4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxamide, or salt thereof.

51. A compound which is (3S,4R)-4-(3,4-dichlorophenyl)-N-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide, or salt thereof.

52. A compound which is (3S,4R)-N-((S)-l-m-tolylethyl>4-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide, or salt thereof.

53. A compound which is (3S,4R)-4-(4-ethylphenyl>N-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide, or salt thereof.

54. A compound which is (3S,4R)-N-((S)-l -phenylethyl)-4-(6- (trifluoromethyl)pyridin-3-yl)pyrrolidine-3-carboxamide, or salt thereof.

55. A compound which is (3S,4S)-N-((S)-l-phenylethyl>4-(5- (trifluoromethyl)furan-2-yl)pyrrolidine-3-carboxamide, or salt thereof.

56. A compound which is (3S,4R)-N-((S)-l-(3-methoxyphenyl)ethyl>4-(6- (trifluoromethyl)pyridin-3-yl)pyrrolidine-3-carboxamide, or salt thereof.

57. A compound which is (3S,4S)-4-(5-chlorothiophen-2-yl)-N-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide, or salt thereof.

58. A compound which is (3S,4S)-N-((S)-l-(3-methoxyphenyl)ethyl>4-(5- (trifluoromethyl)furan-2-yl)pyrrolidine-3-carboxamide, or salt thereof.

59. A compound which is (3S,4S)-4-(5-chlorofuran-2-yl)-N-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide, or salt thereof.